WO2002081628A2 - Modulation of gene expression associated with inflammation proliferation and neurite outgrowth, using nucleic acid based technologies - Google Patents

Modulation of gene expression associated with inflammation proliferation and neurite outgrowth, using nucleic acid based technologies Download PDF

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WO2002081628A2
WO2002081628A2 PCT/US2002/010512 US0210512W WO02081628A2 WO 2002081628 A2 WO2002081628 A2 WO 2002081628A2 US 0210512 W US0210512 W US 0210512W WO 02081628 A2 WO02081628 A2 WO 02081628A2
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nucleic acid
acid molecule
enzymatic nucleic
enzymatic
rna
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WO2002081628A3 (en
WO2002081628A8 (en
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Lawrence Blatt
Bharat Chowrira
Peter Haeberli
James Mcswiggen
Kathy Fosnaugh
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Ribozyme Pharmaceuticals, Incorporated
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Priority claimed from US09/827,395 external-priority patent/US20030113891A1/en
Priority to AU2002307099A priority Critical patent/AU2002307099A1/en
Priority to EP02763926A priority patent/EP1386004A4/en
Priority to US10/471,271 priority patent/US20070026394A1/en
Application filed by Ribozyme Pharmaceuticals, Incorporated filed Critical Ribozyme Pharmaceuticals, Incorporated
Priority to US10/206,693 priority patent/US20050261212A1/en
Publication of WO2002081628A2 publication Critical patent/WO2002081628A2/en
Publication of WO2002081628A3 publication Critical patent/WO2002081628A3/en
Priority to US10/430,882 priority patent/US20030203870A1/en
Publication of WO2002081628A8 publication Critical patent/WO2002081628A8/en
Priority to US10/923,142 priority patent/US20050182008A1/en
Priority to US11/255,139 priority patent/US20060154271A1/en

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Definitions

  • the present invention provides compounds, compositions, and methods for the study, diagnosis, and treatment of conditions relating to the expression of NOGO and NOGO receptor genes.
  • the invention provides nucleic acid molecules that are used to modulate the expression of NOGO and NOGO receptor gene products.
  • the present invention further relates to therapeutic compositions and methods for the treatment or diagnosis of diseases or conditions related to IKK gamma (D KG) and PKR levels, such as cancer, inflammatory, and autoimmune diseases and/or disorders.
  • the present invention also relates to therapeutic compositions and methods for the treatment or diagnosis of diseases or conditions related to allergic response.
  • the invention provides compositions and methods for the treatment of diseases or conditions related to levels of factors involved in allergic conditions such as asthma, for example prostaglandin D2 receptor (PTGDR), prostaglandin D2 synthetase (PTGDS) and adenosine Al receptor (ADORA1).
  • PAGDR prostaglandin D2 receptor
  • PSGDS prostaglandin D2 synthetase
  • ADORA1 adenosine Al receptor
  • ⁇ on-neuronal glial cells of the C ⁇ S including oligodendrocytes and astrocytes, have been shown to inhibit the axonal growth of dorsal root ganglion neurons in culture (Schwab and Thoenen,1985, J Neurosci., 5, 2415- 2423).
  • Cultured dorsal root ganglion cells can extend their axons across glial cells from the peripheral nervous system, (ie; Schwann cells), but are inhibited by oligodendrocytes and myelin ofthe C ⁇ S (Schwab and Caroni, 1988, J. Neurosci., 8, 2381-2393).
  • the non-conducive properties of C ⁇ S tissue in adult vertebrates is thought to result from the existence of inhibitory factors rather than the lack of growth factors.
  • the identification of proteins with neurite outgrowth inhibitory or repulsive properties include ⁇ I- 35, ⁇ I-250 (Caroni and Schwab, 1988, Neuron, 1, 85-96), myelin-associated glycoprotein (Genbank Accession No M29273), tenascin-R (Genbank Accession No X98085), and NG-2 (Genbank Accession No X61945).
  • Monoclonal antibodies (mAb IN-1) raised against NI- 35/250 have been shown to partially neutralize the growth inhibitory effect of CNS myelin and oligodendrocytes.
  • IN-1 treatment in vivo has resulted in long distance fiber regeneration in lesioned adult mammalian CNS tissue (Weibel et al., 1994, Brain Res., 642, 259-266). Additionally, IN-1 treatment in vivo has resulted in the recovery of specific reflex and locomotor functions after spinal cord injury in adult rats (Bregman et al., 1995, Nature, 378, 498-501).
  • NOGO-A Genbank Accession No AJ242961
  • NOGO-B the rat complementary DNA encoding NI-220/250
  • NOGO-C the rat complementary DNA encoding NI-220/250
  • Recombinant NOGO-A inhibits neurite outgrowth from dorsal root ganglia and the spreading of 3T3 firboblasts.
  • Monoclonal antibody IN-1 recognizes NOGO-A and neutralizes NOGO-A inhibition of neuronal growth in vitro.
  • the NOGO amino-terminal region shows no significant homology to any known protein, while the carboxy-terminal tail shares homology with neuroendocrine-specific proteins and other members of the reticulon gene family.
  • the carboxy-terminal tail contains a consensus sequence that may serve as an endoplasmic-reticulum retention region.
  • NOGO a membrane associated protein comprising a putative large extracellular domain of 1,024 residues with seven predicted N-linked glycosylation sites, two or three transmembrane domains, and a short carboxy-terminal region of 43 residues.
  • This cDNA clone encodes a protein that matches all six of the peptide sequences derived from bovine NOGO.
  • Grandpre et al, supra demonstrate that NOGO expression is predominantly associated with the CNS and not the peripheral nervous system (PNS).
  • PNS peripheral nervous system
  • NOGO oligodentrocytes
  • An active domain of NOGO has been identified, defined as residues 31-55 of a hydrophilic 66-residue lumenal/extracellular domain.
  • a synthetic fragment corresponding to this sequence exhibits growth-cone collapsing and outgrowth inhibiting activities (Grandpre et al, supra).
  • NOGO-66 A receptor for the NOGO-A extracellular domain (NOGO-66) is described in Fournier et al, 2001, Nature, 409, 341-346. Fournier et al, have shown that isolated NOGO-66 inhibits axonal extension but does not alter non-neuronal cell morphology. The receptor identified has a high affinity for soluble NOGO-66, and is expressed as a glycophosphatidylinostitol-linked protein on the surface of CNS neurons. Furthermore, the expression of the NOGO-66 receptor in neurons that are NOGO insensitive results in NOGO dependent inhibition of axonal growth in these cells.
  • Nuclear factor kappa B is a multiunit transcription factor which regulates the expression of genes involved in a number of physiologic and pathologic processes.
  • NFKB is a key component of the TNF signaling pathway. These processes include, but are not limited to: apoptosis, immune, inflammatory and acute phase responses.
  • the REL-A gene product (a.k.a. RelA or p65), and p50 subunits of NFKB, have been implicated in the induction of inflammatory responses and cellular transformation.
  • NFKB exists in the cytoplasm as an inactive heterodimer of the p50 and p65 subunits. NFKB is complexed with an inhibitory protein complex, IkappaB (IKK complex), until activated by the appropriate stimuli. NFKB activation can occur following stimulation of a variety of cell types by inflammatory mediators, for example TNF and EL-1, and reactive oxygen intermediates. In response to induction, NFKB can stimulate production of pro- inflammatory cytokines such as TNF- alpha, IL-1 -beta, IL-6 and iNOS, thereby perpetuating a positive feedback loop.
  • IKK complex inhibitory protein complex
  • NFKB appears to play a role in a number of disease processes including: ischemia/reperfusion injury (CNS and myocardial), glomerulonephritis, sepsis, allergic airway inflammation, inflammatory bowel disease, infection, arthritis, and cancer.
  • NFKB nuclear DNA-binding protein
  • NFKB NFKB
  • the activity first described as NFKB is a heterodimer of p49 or p50 with p65.
  • the p49 and p50 subunits of NFKB (encoded by the NF-kappa B2 or NF kappa BI genes, respectively) are generated from the precursors NFKBl (pi 05) or NFKB2 (pi 00).
  • the p65 subunit of NFKB (now termed REL-A) is encoded by the rel- A locus.
  • heterodimers of NFKB2/RelA act with Tat-I to activate transcription of the HIV genome, while NFKBl/RelA (p50/p65) heterodimers have little effect (Liu et al, 1992, J. Virol, 66, 3883- 3887).
  • blocking rel A gene expression with antisense oligonucleotides specifically blocks embryonic stem cell adhesion; blocking NFKBl gene expression with antisense oligonucleotides had no effect on cellular adhesion (Narayanan et al, 1993, Mol. Cell. Biol, 13, 3802-3810).
  • NFKB the promiscuous role initially assigned to NFKB in transcriptional activation (Lenardo, and Baltimore, 1989, Cell, 58, 227-229) represents the sum of the activities of the rel family of DNA-binding proteins. This conclusion is supported by recent transgenic "knock-out" mice of individual members of the rel family. Such "knock-outs" show few developmental defects, suggesting that essential transcriptional activation functions can be performed by more than one member ofthe rel family.
  • NFkB is required for phorbol ester-mediated induction of IL-6 (Kitajima, et al, 1992, Science, 258, 1792-5) and IL-8 (Kunsch and Rosen, 1993, Mol. Cell. Biol, 13, 6137-46).
  • NFkB is required for induction of the adhesion molecules ICAM-1 (Eck, et al, 1993, Mol. Cell. Biol, 13, 6530-6536), VCAM-1 (Shu et al, supra), and E-selectin (Read, et al, 1994, J. Exp. Med., 179, 503-512) on endothelial cells.
  • NFkB is involved in the induction of the integrin subunit, CD 18, and other adhesive properties of leukocytes (Eck et al, 1993 supra).
  • HER2/Neu overexpression induces NFKB via a PI3 -kinase/ Akt pathway involving calpain-mediated degradation of IKB-alpha.
  • Breast cancer has been shown to typify the aberrant expression of NFKB/REL factors (Pianetti et al, 2001, Oncogene, 20, 1287-1299; Sovak et ⁇ /., 1999, J Clin. Invest., 100, 2952-2960).
  • NFKB has been shown to regulate cyclooxygenase-2 expression and cell proliferation in human gastric cancer cells (Joo Weon et al, 2001, Laboratory Investigation, 81, 349-360).
  • NFKB is integrally involved in the induction of cytokines and adhesion molecules by inflammatory mediators and is involved in the transformation of cancerous cells.
  • Glucocorticoid receptor inhibits NFKB-mediated induction of IL-6 (Ray and Prefontaine, 1994 Proc. Natl Acad. Sci USA, 91, 752-756).
  • the IKK complex that sequesters NFKB in the cytoplasm comprises D appaB (I ⁇ B) proteins (I ⁇ B-alpha, I ⁇ B-beta, I ⁇ B-epsilon, pl05, and plOO).
  • I ⁇ B D appaB
  • the phosphorylation of I ⁇ B proteins results in the release of NFKB from the I ⁇ B complex which is transported to the nucleus via the unmasking of nuclear translocation signals.
  • Phosphorylation marks IkB proteins for ubiquitination and degradation via the proteosome pathway.
  • IKK IKB kinase
  • IKKl IKB kinase
  • IKK2 IKB kinase-beta
  • IKK-gamma a protein that is critical for the assembly of the IKK complex.
  • IKK-gamma directly binds to IKK-beta and is required for activation of NFKB, for example by TNF-alpha, IL-1-beta, lipopolysaccharide, phorbol 12-myristate 13-acetate, the human T-cell lympho trophic virus (HTLV-1), or double stranded RNA. Genomic rearrangements in IKK-gamma have been shown to impair NFKB activation and result in incontinentia pigmenti.
  • IKK-associated protein IKK-associated protein
  • RNA-dependent protein kinase PKR is a signal transducer for NFKB and IFN regulatory factor- 1.
  • PKR is required for activation of NFKB by IFN-gamma via a STAT-1 independent pathway (Amitabha et al, 2001, J. Immunol, 166, 6170-6180).
  • the induction of NFKB by PKR takes place though phosphorylation of I ⁇ B-alpha, and appears not to require the catalytic activity of PKR, thereby proceeding independently of the dsRNA-binding properties of PKR (Ishii et al, 2001, Oncogene, 20, 1900-1912).
  • PKR also plays an important role in the regulation of protein synthesis by modulating the activity of eukaryotic initiation factor 2 (eIF-2-alpha) through interferon induction.
  • eIF-2-alpha eukaryotic initiation factor 2
  • Kamiya, JP 2000253884 describes specific antisense oligonucleotides for inhibiting I ⁇ B-kinase subunit expression.
  • Krappmann et al, 2001, J. Biol Chem. describe specific antisense oligonucleotides to IKK-gamma.
  • Asthma is a chronic inflammatory disorder of the lungs characterized by airflow obstruction, bronchial hyper-responsiveness, and airway inflammation.
  • T-lymphocytes that produce T H 2 cytokines and eosinophilic leukocytes infiltrate the airways.
  • BAL bronchial alveolar lavage
  • mast cells Upon allergen challenge, mast cells are activated by cross-linked IgE-allergen complexes. Large amounts of prostaglandin D2 (PGD2), the major cyclooxygenase product of arachidonic acid are released. PGD2 is generated from PGH2 via the activity of prostaglandin D2 synthetase (PTGDS). PGD2 receptors and adenosine Al receptors are present in the lungs and airway along with various other tissues in response to allergic stimuli (Howarth, 1997, Allergy, 52, 12).
  • PGD2 prostaglandin D2
  • PGD2 receptors and adenosine Al receptors are present in the lungs and airway along with various other tissues in response to allergic stimuli (Howarth, 1997, Allergy, 52, 12).
  • DP PGD2 receptor
  • PGD2 receptor DP is a heterotrimeric GTP- binding protein-coupled, rhodopsin-type receptor specific for PGD2 (Hirata et al, 1994, PNAS USA., 91, 11192). These mice fail to develop airway hyperreactivity and have greatly reduced eosinophil infiltration and cytokine accumulation in response to allergens.
  • PGD2 prostaglandin D2 receptor
  • the invention features novel nucleic acid-based molecules, for example, enzymatic nucleic acid molecules, allozymes, antisense nucleic acids, 2-5A antisense chimeras, triplex forming oligonucleotides, decoy RNA, dsRNA, siRNA, aptamers, and antisense nucleic acids containing RNA cleaving chemical groups, and methods to modulate gene expression; for example, gene(s) encoding prostaglandin D2 receptor (PTGDR), prostaglandin D2 synthetase (PTGDS), and adenosine receptors (AR) such as adenosine receptor Al (ADORA1), A2a, A2b, and A3; gene(s) encoding NOGO-A, NOGO-B, NOGO-C, NI-35, NI-220, NI-250, myelin-associated glycoprotein, tenascin-R, NG-2 and/or their
  • the instant invention features nucleic-acid based techniques to inhibit the expression of NOGO-A (Accession No. AJ251383), NOGO-B (Accession No. AJ251384), and or NOGO-C (Accession No. AJ251385), NOGO-66 receptor (Accession No AF283463, Fournier et al, 2001, Nature, 409, 341-346), NI-35, NI-220, and/or NI-250, myelin-associated glycoprotein (Genbank Accession No M29273), tenascin-R (Genbank Accession No X98085), and NG-2 (Genbank Accession No X61945).
  • NOGO-A Accession No. AJ251383
  • NOGO-B Accession No. AJ251384
  • NOGO-C Accession No. AJ251385
  • NOGO-66 receptor Accesion No AF283463, Fournier et al, 2001, Nature, 409,
  • the invention features one or more enzymatic nucleic acid-based molecules and methods that independently or in combination modulate the expression of gene(s) encoding a member of the IKB kinase IKK complex or PKR.
  • the invention features nucleic acid-based molecules and methods that modulate the expression of a member of the IKB kinase IKK complex, for example IKK-alpha (IKKl), IKK-beta (IKK2), or IKK- gamma (IKK ⁇ ) and/or a protein kinase PKR protein, such as IKK-alpha (IKKl) gene (Genbank Accession No.
  • IKK-beta (IKK2) gene for example (Genbank Accession No.AF080158), IKK-gamma (IKK ⁇ ) gene, for example (Genbank Accession No. NM_003639), and protein kinase PKR gene, for example (Genbank Accession No. NM_002759).
  • IKK-gamma is also known as NEMO/ IKKAPl.
  • the various aspects and embodiments are also directed to other genes which encode other subunits of the IKK complex, such as IKK-alpha (IKKl) or IKK- beta (IKK2).
  • Those additional genes can be analyzed for target sites using the methods described for IKK-gamma or PKR.
  • the inhibition and the effects of such inhibition of the other genes can be performed as described herein.
  • an enzymatic nucleic acid molecule of the invention is in a hammerhead, Inozyme, Zinzyme, DNAzyme, Amberzyme, or G-cleaver configuration.
  • a nucleic acid molecule of the invention comprises between 8 and 100 bases complementary to the RNA of the target gene. In another embodiment, a nucleic acid molecule of the invention comprises between 14 and 24 bases complementary to a RNA molecule ofthe target gene.
  • an enzymatic nucleic acid molecule, antisense nucleic acid molecule, 2-5 A antisense chimera, triplex forming oligonucleotide, decoy RNA, dsRNA, siRNA, aptamer, or antisense nucleic acids containing RNA cleaving chemical groups of the invention is chemically synthesized.
  • an enzymatic nucleic acid molecule, antisense nucleic acid molecule, 2-5A antisense chimera, triplex forming oligonucleotide, decoy RNA, dsRNA, siRNA, aptamer, or antisense nucleic acids containing RNA cleaving chemical groups of the invention comprises at least one 2'-sugar modification.
  • an enzymatic nucleic acid molecule, antisense nucleic acid molecule, 2-5A antisense chimera, triplex forming oligonucleotide, decoy RNA, dsRNA, siRNA, aptamer, or antisense nucleic acids containing RNA cleaving chemical groups of the invention comprises at least one nucleic acid base modification.
  • an enzymatic nucleic acid molecule, antisense nucleic acid molecule, 2-5A antisense chimera, triplex forming oligonucleotide, decoy RNA, dsRNA, siRNA, aptamer, or antisense nucleic acids containing RNA cleaving chemical groups of the invention comprises at least one phosphate backbone modification.
  • the invention features a mammalian cell, for example a human cell, including the nucleic acid molecule ofthe invention.
  • the invention features a method of reducing target gene expression or activity in a cell, comprising contacting the cell with a nucleic acid molecule of the invention, such as an enzymatic nucleic acid molecule, antisense nucleic acid molecule, 2-5A antisense chimera, triplex forming oligonucleotide, decoy RNA, dsRNA, siRNA, aptamer, or antisense nucleic acids containing RNA cleaving chemical groups, under conditions suitable for the reduction.
  • a nucleic acid molecule of the invention such as an enzymatic nucleic acid molecule, antisense nucleic acid molecule, 2-5A antisense chimera, triplex forming oligonucleotide, decoy RNA, dsRNA, siRNA, aptamer, or antisense nucleic acids containing RNA cleaving chemical groups, under conditions suitable for the reduction.
  • the invention features a method of treatment of a patient having a condition associated with the level of a target gene, such prostaglandin D2 receptor (PTGDR), prostaglandin D2 synthetase (PTGDS), adenosine receptors (AR) such as adenosine receptor Al (ADORA1), A2a, A2b, and A3, NOGO-A, NOGO-B, NOGO-C, NI- 35, NI-220, NI-250, myelin-associated glycoprotein, tenascin-R, NG-2 and/or their corresponding receptors, an DcappaB kinase (IKK) subunit and or protein kinase PKR, comprising contacting cells of the patient with an enzymatic nucleic acid molecule of the invention, under conditions suitable for the treatment.
  • a target gene such as prostaglandin D2 receptor (PTGDR), prostaglandin D2 synthetase (PTGDS), aden
  • a method of treatment of a patient having a condition associated with the level of a target gene such prostaglandin D2 receptor (PTGDR), prostaglandin D2 synthetase (PTGDS), adenosine receptors (AR) such as adenosine receptor Al (ADORA1), A2a, A2b, and A3, NOGO-A, NOGO-B, NOGO-C, NI-35, NI-220, NI-250, myelin-associated glycoprotein, tenascin-R, NG-2 and/or their corresponding receptors, an DcappaB kinase (IKK) subunit and/or protein kinase PKR is featured, wherein the method further comprises the use of one or more drug therapies under conditions suitable for the treatment.
  • PPGDR prostaglandin D2 receptor
  • PSGDS prostaglandin D2 synthetase
  • AR adenosine receptors
  • ADORA1 adenos
  • the invention features a method of cleaving a RNA molecule of a target gene, such prostaglandin D2 receptor (PTGDR), prostaglandin D2 synthetase (PTGDS), adenosine receptors (AR) such as adenosine receptor Al (ADORA1), A2a, A2b, and A3, NOGO-A, NOGO-B, NOGO-C, NI-35, NI-220, NI-250, myelin-associated glycoprotein, tenascin-R, NG-2 and/or their corresponding receptors, an DcappaB kinase (IKK) subunit and/or protein kinase PKR gene, comprising contacting an enzymatic nucleic acid molecule of the invention with a RNA molecule of the corresponding gene under conditions suitable for the cleavage, for example, wherein the cleavage is carried out in the presence of a divalent cation, such as Mg
  • a nucleic acid molecule of the invention comprises a cap structure, for example a 3',3'-linked or 5',5'-linked deoxyabasic ribose derivative, wherein the cap structure is at the 5'-end, or 3'-end, or both the 5'-end and the 3'-end ofthe enzymatic nucleic acid molecule.
  • the invention features an expression vector comprising a nucleic acid sequence encoding at least one nucleic acid molecule of the invention, in a manner which allows expression ofthe nucleic acid molecule.
  • the invention features a mammalian cell, for example, a human cell, including an expression vector ofthe invention.
  • the expression vector of the invention further comprises a sequence for an antisense nucleic acid molecule complementary to a RNA molecule of a target gene, such prostaglandin D2 receptor (PTGDR), prostaglandin D2 synthetase (PTGDS), adenosine receptors (AR) such as adenosine receptor Al (ADORA1), A2a, A2b, and A3, NOGO-A, NOGO-B, NOGO-C, NI-35, NI-220, NI-250, myelin-associated glycoprotein, tenascin-R, NG-2 and/or their corresponding receptors, an DcappaB kinase (IKK) subunit and or protein kinase PKR gene.
  • PSGDR prostaglandin D2 receptor
  • PSGDS prostaglandin D2 synthetase
  • an expression vector of the invention comprises a nucleic acid sequence encoding two or more nucleic acid molecules, such as enzymatic nucleic acid molecules, antisense, aptamers, decoys, siRNA, or 2-5 A chimeras which can be the same or different.
  • the method of treatment features an enzymatic nucleic acid molecule of the invention comprises at least five ribose residues, at least ten 2'-O-methyl modifications, and a 3'- end modification, such as a 3 '-3' inverted abasic moiety.
  • an enzymatic nucleic acid molecule or antisense nucleic acid molecule of the invention further comprises phosphorothioate linkages on at least three of the 5' terminal nucleotides.
  • the invention features a method of administering to a mammal, for example a human, an enzymatic nucleic acid molecule, antisense nucleic acid molecule, 2- 5 A antisense chimera, triplex forming oligonucleotide, decoy RNA, dsRNA, siRNA, aptamer, or antisense nucleic acid containing RNA cleaving chemical groups of the invention, comprising contacting the mammal with the nucleic acid molecule under conditions suitable for the administration, for example, in the presence of a delivery reagent such as a lipid, cationic lipid, phospholipid, or liposome.
  • a delivery reagent such as a lipid, cationic lipid, phospholipid, or liposome.
  • the invention features a method of administering to a mammal an enzymatic nucleic acid molecule, antisense nucleic acid molecule, 2-5A antisense chimera, triplex forming oligonucleotide, decoy RNA, dsRNA, siRNA, aptamer, or antisense nucleic acid containing RNA cleaving chemical groups ofthe indention in conjunction with a therapeutic agent, comprising contacting the mammal, for example a human, with the nucleic acid molecule and the therapeutic agent under conditions suitable for the administration.
  • the invention features the use of an enzymatic nucleic acid molecule, which can be in a hammerhead, NCH, G-cleaver, Amberzyme, Zinzyme, and or
  • DNAzyme motif to down-regulate the expression of a a target gene, such as prostaglandin
  • D2 receptor PSGDR
  • PSGDS prostaglandin D2 synthetase
  • adenosine receptors AR
  • AD ⁇ RA1 adenosine receptor Al
  • A2a, A2b, and A3 NOGO-A, NOGO-B, NOGO-C, NI-35, NI-220, NI-250, myelin-associated glycoprotein, tenascin-R, NG-2 and/or their corresponding receptors, an DcappaB kinase (JKK) subunit and/or protein kinase PKR gene.
  • JKK DcappaB kinase
  • inhibitor By “inhibit”, “down-regulate”, or “reduce”, it is meant that the expression of the gene, or level of RNA molecules or equivalent RNA molecules encoding one or more proteins or protein subunits, or activity of one or more proteins or protein subunits, such as prostaglandin D2 receptor (PTGDR), prostaglandin D2 synthetase (PTGDS), adenosine receptors (AR) such as adenosine receptor Al (ADORAl), A2a, A2b, and A3, NOGO-A, NOGO-B, NOGO-C, NI-35, NI-220, NI-250, myelin-associated glycoprotein, tenascin-R, NG-2 and/or their corresponding receptors, an DcappaB kinase (IKK) subunit and/or protein kinase PKR subunits, is reduced below that observed in the absence of the nucleic acid molecules of the invention.
  • PSGDR prostag
  • inhibition, down-regulation or reduction with an enzymatic nucleic acid molecule is below that level observed in the presence of an enzymatically inactive or attenuated molecule that is able to bind to the same site on the target RNA molecule, but is unable to cleave that RNA molecule.
  • inhibition, down-regulation, or reduction with antisense oligonucleotides is below that level observed in the presence of, for example, an oligonucleotide with scrambled sequence or with mismatches.
  • inhibition, down-regulation, or reduction of the target gene with a nucleic acid molecule of the instant invention is greater in the presence of the nucleic acid molecule than in its absence.
  • up-regulate is meant that the expression of a gene, or level of RNA molecules or equivalent RNA molecules encoding one or more proteins, protein subunits, or activity of one or more proteins or protein subunits, such as a target gene, such as prostaglandin D2 receptor (PTGDR), prostaglandin D2 synthetase (PTGDS), adenosine receptors (AR) such as adenosine receptor Al (ADORAl), A2a, A2b, and A3, NOGO-A, NOGO-B, NOGO-C, NI- 35, NI-220, NI-250, myelin-associated glycoprotein, tenascin-R, NG-2 and/or their corresponding receptors, an DcappaB kinase (IKK) subunit and/or protein kinase PKR subunits, is greater than that observed in the absence of the nucleic acid molecules of the invention.
  • PGPDR prostaglandin D2 receptor
  • a gene such as prostaglandin D2 receptor (PTGDR), prostaglandin D2 synthetase (PTGDS), adenosine receptors (AR) such as adenosine receptor Al (ADORAl), A2a, A2b, and A3, NOGO-A, NOGO-B, NOGO-C, NI- 35, NI-220, NI-250, myelin-associated glycoprotein, tenascin-R, NG-2 and/or their corresponding receptors, an DcappaB kinase (IKK) subunit and or protein kinase PKR gene, can be increased in order to treat, prevent, ameliorate, or modulate a pathological condition caused or exacerbated by an absence or low level of gene expression.
  • PPGDR prostaglandin D2 receptor
  • PSGDS prostaglandin D2 synthetase
  • AR adenosine receptors
  • NOGO-A, NOGO-B, NOGO-C
  • module is meant that the expression ofthe gene, or level of RNA molecules or equivalent RNA molecules encoding one or more protein subunits, or activity of one or more protein subunits is up-regulated or down-regulated, such that the expression, level, or activity is greater than or less than that observed in the absence of a nucleic acid molecule of the invention.
  • enzymatic nucleic acid molecule it is meant a nucleic acid molecule that has complementarity in a substrate binding region to a specified gene target, and also has an enzymatic activity that is active to specifically cleave target a RNA molecule. That is, the enzymatic nucleic acid molecule is able to intermolecularly cleave a RNA molecule and thereby inactivate a target RNA molecule. These complementary regions allow sufficient hybridization of an enzymatic nucleic acid molecule to a target RNA molecule and thus permit cleavage.
  • nucleic acids can be modified at the base, sugar, and/or phosphate groups.
  • enzymatic nucleic acid is used interchangeably with phrases such as ribozymes, catalytic RNA, enzymatic RNA, catalytic DNA, aptazyme or aptamer-binding ribozyme, regulatable ribozyme, catalytic oligonucleotides, nucleozyme, DNAzyme, RNA enzyme, endoribonuclease, endonuclease, minizyme, leadzyme, oligozyme or DNA enzyme. All of these terminologies describe nucleic acid molecules with enzymatic activity.
  • enzymatic nucleic acid molecules described in the instant application are not limiting in the invention and those skilled in the art will recognize that all that is important in an enzymatic nucleic acid molecule of this invention is that it has a specific substrate binding site that is complementary to one or more of the target nucleic acid regions, and that it have nucleotide sequences within or surrounding that substrate binding site which impart a nucleic acid cleaving and/or ligation activity to the molecule (Cech et al, U.S. Patent No. 4,987,071; Cech et al, 1988, 260 JAMA 3030).
  • nucleic acid molecule as used herein is meant a molecule having nucleotides.
  • the nucleic acid can be single, double, or multiple stranded and can comprise modified or unmodified nucleotides or non-nucleotides or various mixtures and combinations thereof.
  • Exemplary nucleic acid molecules of the invention include enzymatic nucleic acid molecules, allozymes, antisense nucleic acids, 2-5A antisense chimeras, triplex forming oligonucleotides, decoy RNA, dsRNA, siRNA, aptamers, and/or antisense nucleic acids containing RNA cleaving chemical groups.
  • enzymatic portion or “catalytic domain” is meant that portion region of the enzymatic nucleic acid molecule essential for cleavage of a nucleic acid substrate (for example see Figures 1-4).
  • substrate binding arm or “substrate binding domain” is meant that portion/region of a enzymatic nucleic acid that is able to interact, for example via complementarity ⁇ i.e., able to base-pair with), with a portion of its substrate.
  • complementarity can be 100%, but can be less if desired.
  • as few as 10 bases out of 14 can be base-paired (see for example Werner and Uhlenbeck, 1995, Nucleic Acids Research, 23, 2092-2096; Hammann et al, 1999, Antisense and Nucleic Acid Drug Dev., 9, 25-31). Examples of such arms are shown generally in Figures 1-4.
  • these arms contain sequences within an enzymatic nucleic acid that are intended to bring enzymatic nucleic acid and target RNA together through complementary base-pairing interactions.
  • the enzymatic nucleic acid of the invention can have binding arms that are contiguous or non-contiguous and can be of varying lengths.
  • the length ofthe binding arm(s) can be greater than or equal to four nucleotides and of sufficient length to stably interact with a target RNA; in one embodiment they can be 12- 100 nucleotides; in another embodiment they can be 14-24 nucleotides long (see for example Werner and Uhlenbeck, supra; Hamman et al, supra; Hampel et al, EP0360257; Berzal- Herranze et al, 1993, EMBO J., 12, 2567-73) or between 8 and 14 nucleotides long.
  • the design is such that the length of the binding arms are symmetrical ⁇ i.e., each of the binding arms is of the same length; e.g., four and four, five and five nucleotides, or six and six nucleotides, or seven and seven nucleotides long) or asymmetrical ⁇ i.e., the binding arms are of different length; e.g., three and five, six and three nucleotides; three and six nucleotides long; four and five nucleotides long; four and six nucleotides long; four and seven nucleotides long; and the like).
  • Inozyme or "NCH” motif or configuration is meant, an enzymatic nucleic acid molecule comprising a motif as is generally described as NCH Rz in Figure 1.
  • Inozymes possess endonuclease activity to cleave RNA substrates having a cleavage triplet NCH/, where N is a nucleotide, C is cytidine and H is adenosine, uridine or cytidine, and / represents the cleavage site.
  • H is used interchangeably with X.
  • Inozymes can also possess endonuclease activity to cleave RNA substrates having a cleavage triplet NCN/, where N is a nucleotide, C is cytidine, and / represents the cleavage site.
  • "I” in Figure 1 represents an Inosine nucleotide, including a ribo-Inosine or xylo-Inosine nucleoside.
  • G-cleaver motif or configuration is meant, an enzymatic nucleic acid molecule comprising a motif as is generally described as G-cleaver Rz in Figure 1.
  • G-cleavers possess endonuclease activity to cleave RNA substrates having a cleavage triplet NYN/, where N is a nucleotide, Y is uridine or cytidine and / represents the cleavage site.
  • G-cleavers can be chemically modified as is generally shown in Figure 1.
  • Amberzyme motif or configuration an enzymatic nucleic acid molecule comprising a motif as is generally described in Figure 2.
  • Amberzymes possess endonuclease activity to cleave RNA substrates having a cleavage triplet NG/N, where N is a nucleotide, G is guanosine, and / represents the cleavage site.
  • Amberzymes can be chemically modified to increase nuc lease stability through substitutions as are generally shown in Figure 2.
  • differing nucleoside and/or non-nucleoside linkers can be used to substitute the 5'- gaaa-3' loops shown in the figure.
  • Amberzymes represent a non-limiting example of an enzymatic nucleic acid molecule that does not require a ribonucleotide (2' -OH) group within its own nucleic acid sequence for activity.
  • Zinzyme motif or configuration an enzymatic nucleic acid molecule comprising a motif as is generally described in Figure 3.
  • Zinzymes possess endonuclease activity to cleave RNA substrates having a cleavage triplet including but not limited to YG/Y, where Y is uridine or cytidine, and G is guanosine and / represents the cleavage site.
  • Zinzymes can be chemically modified to increase nuclease stability through substitutions as are generally shown in Figure 3, including substituting 2'-O-methyl guanosine nucleotides for guanosine nucleotides.
  • Zinzymes represent a non- limiting example of an enzymatic nucleic acid molecule that does not require a ribonucleotide (2' -OH) group within its own nucleic acid sequence for activity.
  • DNAzyme' is meant, an enzymatic nucleic acid molecule that does not require the presence of a 2' -OH group within its own nucleic acid sequence for activity.
  • the enzymatic nucleic acid molecule can have an attached linker or linkers or other attached or associated groups, moieties, or chains containing one or more nucleotides with 2'-OH groups.
  • DNAzymes can be synthesized chemically or expressed endogenously in vivo, by means of a single stranded DNA vector or equivalent thereof.
  • DNAzyme An example of a DNAzyme is shown in Figure 4 and is generally reviewed in Usman et al, US patent No., 6,159,714; Chartrand et al, 1995, NAR 23, 4092; Breaker et al, 1995, Chem. Bio. 2, 655; Santoro et al, 1997, PNAS 94, 4262; Breaker, 1999, Nature Biotechnology, 17, 422-423; and Santoro et. al, 2000, J. Am. Chem. Soc, 122, 2433-39.
  • the "10-23" DNAzyme motif is one particular type of DNAzyme that was evolved using in vitro selection (see Santoro et al, supra). Additional DNAzyme motifs can be selected for using techniques similar to those described in these references, and hence, are within the scope ofthe present invention.
  • sufficient length is meant an oligonucleotide of greater than or equal to 3 nucleotides that is of a length great enough to provide the intended function under the expected condition.
  • sufficient length means that the binding arm sequence is long enough to provide stable binding to a target site under the expected binding conditions. The binding arms are not so long as to prevent useful turnover ofthe nucleic acid molecule.
  • stably interact is meant interaction of the oligonucleotides with target nucleic acid ⁇ e.g., by forming hydrogen bonds with complementary nucleotides in the target under physiological conditions) that is sufficient to the intended purpose (e.g., cleavage of target RNA by an enzyme).
  • RNA to NOGO is meant to include those naturally occurring RNA molecules having homology (partial or complete) to NOGO-A, NOGO-B, NOGO-C and/or NOGO receptor proteins or encoding for proteins with similar function as NOGO or NOGO receptor proteins in various organisms, including human, rodent, primate, rabbit, pig, protozoans, fungi, plants, and other microorganisms and parasites.
  • the equivalent RNA sequence also includes in addition to the coding region, regions such as 5 '-untranslated region, 3 '-untranslated region, introns, intron-exon junction and the like.
  • RNA to IKK-gamma is meant to include those naturally occurring RNA molecules having homology (partial or complete) to IKK-gamma proteins or encoding for proteins with similar function as IKK-gamma proteins in various organisms, including human, rodent, primate, rabbit, pig, protozoans, fungi, plants, and other microorganisms and parasites.
  • the equivalent RNA sequence also includes in addition to the coding region, regions such as 5 '-untranslated region, 3 '-untranslated region, introns, intron- exon junction and the like.
  • RNA to PKR is meant to include those naturally occurring RNA molecules having homology (partial or complete) to PKR proteins or encoding for proteins with similar function as PKR proteins in various organisms, including human, rodent, primate, rabbit, pig, protozoans, fungi, plants, and other microorganisms and parasites.
  • the equivalent RNA sequence also includes in addition to the coding region, regions such as 5 '-untranslated region, 3 '-untranslated region, introns, intron-exon junction and the like.
  • RNA molecules having homology are meant to include RNA molecules having homology (partial or complete) to RNA molecules encoding PTGDS proteins or encoding proteins with similar function as PTGDS proteins in various organisms, including human, rodent, primate, rabbit, pig, plants, protozoans, fungi, and other microorganisms and parasites.
  • the equivalent RNA sequence can also include in addition to the coding region, regions such as 5 '-untranslated region, 3 '-untranslated region, introns, intron-exon junction and the like.
  • RNA molecules having homology are meant to include RNA molecules having homology (partial or complete) to RNA molecules encoding PTGDR proteins or encoding proteins with similar function as PTGDR proteins in various organisms, including human, rodent, primate, rabbit, pig, plants, protozoans, fungi, and other microorganisms and parasites.
  • the equivalent RNA sequence can also include in addition to the coding region, regions such as 5 '-untranslated region, 3 '-untranslated region, introns, intron-exon junction and the like.
  • RNA to ADORAl is meant to include RNA molecules having homology (partial or complete) to RNA molecule encoding ADORAl proteins or encoding proteins with similar function as ADORAl proteins in various organisms, including human, rodent, primate, rabbit, pig, plants, protozoans, fungi, and other microorganisms and parasites.
  • the equivalent RNA sequence can also include in addition to the coding region, regions such as 5 '-untranslated region, 3 '-untranslated region, introns, intron-exon junction and the like.
  • nucleotide sequence of two or more nucleic acid molecules is partially or completely identical.
  • antisense nucleic acid a non-enzymatic nucleic acid molecule that binds to target RNA by means of RNA-RNA or RNA-DNA or RNA-PNA (protein nucleic acid; Egholm et al, 1993 Nature 365, 566) interactions and alters the activity of the target RNA (for a review, see Stein and Cheng, 1993 Science 261, 1004 and Woolf et al, US patent No. 5,849,902).
  • antisense molecules are complementary to a target sequence along a single contiguous sequence of the antisense molecule.
  • an antisense molecule can bind to substrate such that the substrate molecule forms a loop, and/or an antisense molecule can bind such that the antisense molecule forms a loop.
  • the antisense molecule can be complementary to two (or even more) non-contiguous substrate sequences or two (or even more) non-contiguous sequence portions of an antisense molecule can be complementary to a target sequence or both.
  • antisense DNA can be used to target RNA by means of DNA-RNA interactions, thereby activating RNase H, which digests the target RNA in the duplex.
  • the antisense oligonucleotides can comprise one or more RNAse H activating region, which is capable of activating RNAse H cleavage of a target RNA.
  • Antisense DNA can be synthesized chemically or expressed via the use of a single stranded DNA expression vector or equivalent thereof.
  • RNase H activating region is meant a region (generally greater than or equal to 4-
  • nucleic acid molecule capable of binding to a target RNA to form a non-covalent complex that is recognized by cellular RNase H enzyme (see for example Arrow et al, US 5,849,902; Arrow et al, US 5,989,912).
  • the RNase H enzyme binds to the nucleic acid molecule-target RNA complex and cleaves the target RNA sequence.
  • the RNase H activating region comprises, for example, phosphodiester, phosphorothioate (at least four of the nucleotides are phosphorothiote substitutions; and in another embodiment, 4-11 of the nucleotides are phosphorothiote substitutions); phosphorodithioate, 5'-thiophosphate, or methylphosphonate backbone chemistry or a combination thereof.
  • the RNase H activating region can also comprise a variety of sugar chemistries.
  • the RNase H activating region can comprise deoxyribose, arabino, fluoroarabino or a combination thereof, nucleotide sugar chemistry.
  • 2-5 A antisense chimera an antisense oligonucleotide containing a 5'- phosphorylated 2'-5'-linked adenylate residue. These chimeras bind to target RNA in a sequence-specific manner and activate a cellular 2-5 A-dependent ribonuclease which, in turn, cleaves the target RNA (Torrence et al, 1993 Proc. Natl. Acad. Sci. USA 90, 1300; Silverman et al, 2000, Methods Enzymol, 313, 522-533; Player and Torrence, 1998, Pharmacol. Ther., 78, 55-113).
  • aptamer or “nucleic acid aptamer” as used herein is meant a nucleic acid molecule that binds specifically to a target molecule wherein the nucleic acid molecule has sequence that is distinct from sequence recognized by the target molecule in its natural setting.
  • an aptamer can be a nucleic acid molecule that binds to a target molecule where the target molecule does not naturally bind to a nucleic acid.
  • the target molecule can be any molecule of interest.
  • the aptamer can be used to bind to a ligand-binding domain of a protein, thereby preventing interaction of the naturally occurring ligand with the protein. This is a non-limiting example and those in the art will recognize that other embodiments can be readily generated using techniques generally known in the art, see for example Gold et al, 1995, Annu. Rev. Biochem., 64, 763; Brody and Gold, 2000, J.
  • triplex forming oligonucleotides an oligonucleotide that can bind to a double-stranded DNA in a sequence-specific manner to form a triple-strand helix. Formation of such triple helix structure has been shown to inhibit transcription of the targeted gene (Duval- Valentin et al, 1992 Proc. Natl. Acad. Sci. USA 89, 504; Fox, 2000, Curr. Med.
  • RNA RNA sequences including but not limited to structural genes encoding a polypeptide.
  • “Complementarity” refers to the ability of a nucleic acid to form hydrogen bond(s) with another RNA molecule by either traditional Watson-Crick or other non-traditional types.
  • the binding free energy for a nucleic acid molecule with its target or complementary sequence is sufficient to allow the relevant function of the nucleic acid to proceed, e.g., enzymatic nucleic acid cleavage, antisense or triple helix inhibition. Determination of binding free energies for nucleic acid molecules is well known in the art (see, e.g., Turner et al, 1987, CSH Symp. Quant. Biol. LH pp.123-133; Frier et al, 1986, Proc.
  • a percent complementarity indicates the percentage of contiguous residues in a nucleic acid molecule that can form hydrogen bonds (e.g., Watson- Crick base pairing) with a second nucleic acid sequence (e.g., 5, 6, 7, 8, 9, 10 out of 10 being 50%, 60%, 70%, 80%), 90%), and 100% complementary).
  • Perfectly complementary means that all the contiguous residues of a nucleic acid sequence will hydrogen bond with the same number of contiguous residues in a second nucleic acid sequence.
  • RNA is meant a molecule comprising at least one ribonucleotide residue.
  • ribonucleotide or “2'-OH” is meant a nucleotide with a hydroxyl group at the 2' position of a ⁇ -D-ribo-furanose moiety.
  • decoy RNA is meant an RNA molecule or aptamer that is designed to preferentially bind to a predetermined ligand. Such binding can result in the inhibition or activation of a target molecule.
  • the decoy RNA or aptamer can compete with a naturally occurring binding target for the binding of a specific ligand. For example, it has been shown that over-expression of HIV trans-activation response (TAR) RNA can act as a "decoy” and efficiently binds HIV tat protein, thereby preventing it from binding to TAR sequences encoded in the HIV RNA (Sullenger et al, 1990, Cell, 63, 601-608).
  • TAR HIV trans-activation response
  • a decoy RNA can be designed to bind to a D2 receptor and block the binding of PTGDS or a decoy RNA can be designed to bind to PTGDS and prevent interaction with the D2 receptor.
  • RNA interference refers to a double stranded nucleic acid molecule capable of RNA interference "RNAi”, see for example Bass,
  • siRNA molecules need not be limited to those molecules containing only RNA, but further encompasses chemically modified nucleotides and non- nucleo tides.
  • allozyme refers to an allosteric enzymatic nucleic acid molecule, see, e.g., George et al, US Patent Nos. 5,834,186 and 5,741,679, Shih et al, US Patent No. 5,589,332, Nathan et al, US Patent No 5,871,914, Nathan and Ellington, International PCT publication No. WO 00/24931, Breaker et al, International PCT Publication Nos. WO 00/26226 and 98/27104, and Sullenger et al, International PCT publication No. WO 99/29842.
  • 2-5A chimera refers to an oligonucleotide containing a 5'-phosphorylated 2'-5'-linked adenylate residue. These chimeras bind to target RNA in a sequence-specific manner and activate a cellular 2-5A- dependent ribonuclease which, in turn, cleaves the target RNA (Torrence et al, 1993 Proc. Natl. Acad. Sci. USA 90, 1300; Silverman et al, 2000, Methods Enzymol, 313, 522-533; Player and Torrence, 1998, Pharmacol. Ther., 78, 55-113).
  • triplex forming oligonucleotides refers to an oligonucleotide that can bind to a double-stranded DNA in a sequence-specific manner to form a triple-strand helix. Formation of such triple helix structure has been shown to inhibit transcription of the targeted gene (Duval-Valentin et al, 1992 Proc. Natl. Acad. Sci. USA 89, 504; Fox, 2000, Curr. Med. Chem., 1, 17-37; Praseuth et. al, 2000, Biochim. Biophys. Acta, 1489, 181-206).
  • Several varieties of naturally-occurring enzymatic RNAs are known presently.
  • enzymatic nucleic acids act by first binding to a target RNA. Such binding occurs through the target binding portion of a enzymatic nucleic acid that is held in close proximity to an enzymatic portion ofthe molecule that acts to cleave the target RNA. Thus, the enzymatic nucleic acid first recognizes and then binds a target RNA through complementary base-pairing, and once bound to the correct site, acts enzymatically to cut the target RNA.
  • RNA Strategic cleavage of such a target RNA will destroy its ability to direct synthesis of an encoded protein. After an enzymatic nucleic acid has bound and cleaved its RNA target, it is released from that RNA to search for another target and can repeatedly bind and cleave new targets.
  • a single ribozyme molecule is able to cleave many molecules of target RNA.
  • the ribozyme is a highly specific inhibitor of gene expression, with the specificity of inhibition depending not only on the base-pairing mechanism of binding to the target RNA, but also on the mechanism of target RNA cleavage. Single mismatches, or base-substitutions, near the site of cleavage can completely eliminate catalytic activity of a ribozyme.
  • the enzymatic nucleic acid molecule is formed in a hammerhead or hairpin motif, but can also be formed in the motif of a hepatitis delta virus, group I intron, group ⁇ intron or RNase P RNA (in association with an RNA guide sequence), Neurospora VS RNA, DNAzymes, NCH cleaving motifs, or G- cleavers.
  • Group fl introns are described by Griffin et al, 1995, Chem. Biol. 2, 761; Michels and Pyle, 1995, Biochemistry 34, 2965; Pyle et al, International PCT Publication No. WO 96/22689; of the Group I intron by Cech et al, U.S. Patent 4,987,071 and of DNAzymes by Usman et al, International PCT Publication No. WO 95/11304; Chartrand et al, 1995, NAR 23, 4092; Breaker et al, 1995, Chem. Bio. 2, 655; Santoro et al, 1997, PNAS 94, 4262, and Beigelman et al, International PCT publication No.
  • WO 99/55857 NCH cleaving motifs are described in Ludwig & Sproat, International PCT Publication No. WO 98/58058; and G-cleavers are described in Kore et al, 1998, Nucleic Acids Research 26, 4116-4120 and Eckstein et al, International PCT Publication No. WO 99/16871. Additional motifs such as the Aptazyme (Breaker et al, WO 98/43993), Amberzyme (Class I motif; Figure 2; Beigelman et al, U.S. Serial No. 09/301,511) and Zinzyme ( Figure 3) (Beigelman et al, U.S. Serial No.
  • nucleic acid molecule of the instant invention can be between 12 and 100 nucleotides in length.
  • enzymatic nucleic acid molecules of the invention are shown in Tables III-XXIII.
  • enzymatic nucleic acid molecules of the invention can be between 15 and 50 nucleotides in length, and in another embodiment between 25 and 40 nucleotides in length, e.g., 34, 36, or 38 nucleotides in length (for example see Jarvis et al, 1996, J. Biol. Chem., 271, 29107-29112).
  • Exemplary DNAzymes ofthe invention are can between 15 and 40 nucleotides in length, and in one embodiment, between 25 and 35 nucleotides in length, e.g., 29, 30, 31, or 32 nucleotides in length (see, e.g., Santoro et al, 1998, Biochemistry, 37, 13330-13342; Chartrand et al, 1995, Nucleic Acids Research, 23, 4092-4096).
  • Exemplary antisense molecules of the invention can be between 15 and 75 nucleotides in length, and in one embodiment between 20 and 35 nucleotides in length, e.g., 25, 26, 27, or 28 nucleotides in length (see for example Woolf et al, 1992, PNAS, 89, 7305-7309; Milner et al, 1997, Nature Biotechnology, 15, 537-541).
  • Exemplary triplex forming oligonucleotide molecules of the invention are between 10 and 40 nucleotides in length, and in one embodiment are between 12 and 25 nucleotides in length, e.g., 18, 19, 20, or 21 nucleotides in length (see for example Maher et al, 1990, Biochemistry, 29, 8820-8826; Strobel and Dervan, 1990, Science, 249, 73-75).
  • Those skilled in the art will recognize that all that is required is for the nucleic acid molecule to be of length and conformation sufficient and suitable for the nucleic acid molecule to catalyze a reaction contemplated herein.
  • the length of the nucleic acid molecules ofthe instant invention are not limiting within the general limits stated.
  • a nucleic acid molecule that modulates, for example, down- regulates, the expression of a target gene comprises between 8 and 100 bases complementary to a RNA molecule of prostaglandin D2 receptor (PTGDR), prostaglandin D2 synthetase (PTGDS), adenosine receptors (AR) such as adenosine receptor Al (ADORAl), A2a, A2b, and A3, NOGO-A, NOGO-B, NOGO-C, NI-35, NI-220, NI-250, myelin-associated glycoprotein, tenascin-R, NG-2 and/or their corresponding receptors, an DcappaB kinase (IKK) subunit and/or protein kinase PKR.
  • PAGDR prostaglandin D2 receptor
  • PSGDS prostaglandin D2 synthetase
  • AR adenosine receptors
  • ADORAl adenosine receptor Al
  • a nucleic acid molecule that modulates the expression of a target gene comprises between 14 and 24 bases complementary to a RNA molecule of prostaglandin D2 receptor (PTGDR), prostaglandin D2 synthetase (PTGDS), adenosine receptors (AR) such as adenosine receptor Al (ADORAl), A2a, A2b, and A3, NOGO-A, NOGO-B, NOGO-C, NI-35, NI-220, NI-250, myelin- associated glycoprotein, tenascin-R, NG-2 and/or their corresponding receptors, an DcappaB kinase (IKK) subunit and or protein kinase PKR.
  • PAGDR prostaglandin D2 receptor
  • PSGDS prostaglandin D2 synthetase
  • AR adenosine receptors
  • ADORAl adenosine receptor Al
  • the invention provides a method for producing a class of nucleic acid-based gene modulating agents that exhibit a high degree of specificity for the RNA of a desired target.
  • the enzymatic nucleic acid molecule is can be targeted to a highly conserved sequence region of target RNAs encoding prostaglandin D2 receptor (PTGDR), prostaglandin D2 synthetase (PTGDS), adenosine receptors (AR) such as adenosine receptor Al (ADORAl), A2a, A2b, and A3, NOGO-A, NOGO-B, NOGO-C, NI-35, NI-220, NI-250, myelin-associated glycoprotein, tenascin-R, NG-2 and or their corresponding receptors, an DcappaB kinase (IKK) subunit and/or protein kinase PKR (e.g., prostaglandin D2 receptor (PTGDR)), prostaglandin D2
  • nucleic acid molecules can be delivered exogenously to specific tissue or cellular targets as required.
  • nucleic acid molecules e.g., ribozymes, antisense, aptamers, and/or siRNA
  • the nucleic acid molecules can be expressed from DNA and/or RNA vectors that are delivered to specific cells.
  • cell is used in its usual biological sense, and does not refer to an entire multicellular organism.
  • the cell can, for example, be in vitro, e.g., in cell culture, or present in a multicellular organism, including,, e.g., birds, plants and mammals such as humans, cows, sheep, apes, monkeys, swine, dogs, and cats.
  • the cell may be prokaryotic (e.g., bacterial cell) or eukaryotic (e.g., mammalian or plant cell).
  • NOGO proteins is meant, a protein, protein receptor or a mutant protein derivative thereof, comprising neuronal inhibitor activity, preferably CNS neuronal growth inhibitor activity.
  • IKK-gamma proteins a peptide or protein comprising a IKK-gamma or NEMO/ IKKAPl component of the IKK complex, for example a regulatory IKK subunit involved in the assembly of the high molecular weight IKK complex and/or induction of NFKB.
  • PTK proteins a peptide or protein comprising a protein kinase PKR activity, for example the activation of NFKB.
  • PGPDR proteins is meant, a protein receptor or a mutant protein or peptide derivative thereof, having prostaglandin D2 receptor activity, for example, having the ability to bind prostaglandin D2 and/or having GTP -binding protein coupled activity.
  • PGHDS proteins a prostaglandin synthetase protein or a mutant protein or peptide derivative thereof, having prostaglandin D2 synthetase activity, for example, having the ability to convert PGH2 to PGD2.
  • highly conserved sequence region is meant, a nucleotide sequence of one or more regions in a target gene does not vary significantly from one generation to the other or from one biological system to the other.
  • the nucleic acid-based inhibitors of the invention can be added directly, or can be complexed with cationic lipids, packaged within liposomes, or otherwise delivered to target cells or tissues, for example by pulmonary delivery of an aerosol formulation with an inhaler or nebulizer.
  • the nucleic acid or nucleic acid complexes can be locally administered to relevant tissues ex vivo, or in vivo through inhalation, injection or infusion pump, with or without their incorporation in biopolymers.
  • the enzymatic nucleic acid inhibitors comprise sequences that are complementary to the substrate sequences in Tables III to XXIII. Examples of such enzymatic nucleic acid molecules also are shown in Tables III to XXIII. Examples of such enzymatic nucleic acid molecules consist essentially of sequences defined in these tables.
  • the invention features antisense nucleic acid molecules, siRNA and 2-5 A chimeras including sequences complementary to the substrate sequences shown in
  • nucleic acid molecules can include sequences as shown for the binding arms of the enzymatic nucleic acid molecules in Tables III to XXIII.
  • triplex molecules can be provided targeted to the corresponding DNA target regions, and containing the DNA equivalent of a target sequence or a sequence complementary to the specified target (substrate) sequence.
  • antisense molecules are complementary to a target sequence along a single contiguous sequence of the antisense molecule.
  • an antisense molecule can bind to substrate such that the substrate molecule forms a loop, and/or an antisense molecule can bind such that the antisense molecule forms a loop.
  • the antisense molecule can be complementary to two (or even more) non-contiguous substrate sequences or two (or even more) non-contiguous sequence portions of an antisense molecule can be complementary to a target sequence or both.
  • a core region can, for example, include one or more loop, stem-loop structure, or linker which does not prevent enzymatic activity.
  • underlined regions in the sequences in Tables III, IV, VIII, IX, XIII, XIV, XIX, and XX can be such a loop, stem-loop, nucleotide linker, and/or non-nucleotide linker and can be represented generally as sequence "X".
  • a core sequence for a hammerhead enzymatic nucleic acid can comprise a conserved sequence, such as 5'-CUGAUGAG-3' and 5'-CGAA-3' connected by "X", where X is 5'-GCCGUUAGGC-3' (SEQ ID NO: 13274), or any other Stem fl region known in the art, or a nucleotide and or non-nucleotide linker.
  • nucleic acid molecules of the instant invention such as Inozyme, G-cleaver, amberzyme, zinzyme, DNAzyme, antisense, 2-5A antisense, triplex forming nucleic acid, siRNA and decoy nucleic acids
  • other sequences or non-nucleotide linkers can be present that do not interfere with the function ofthe nucleic acid molecule.
  • Sequence X can be a linker of > 2 nucleotides in length, including 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 26, 30, where the nucleotides can be internally base-paired to form a stem of > 2 base pairs.
  • sequence X can be a non-nucleotide linker.
  • the nucleotide linker X can be a nucleic acid aptamer, such as an ATP aptamer, HIV Rev aptamer (RRE), HIV Tat aptamer (TAR) and others (for a review see Gold et al, 1995, Annu. Rev. Biochem., 64, 763; and Szostak & Ellington, 1993, in The RNA World, ed.
  • nucleic acid aptamer as used herein is meant to indicate a nucleic acid sequence capable of interacting with a ligand.
  • the ligand can be any natural or a synthetic molecule, including but not limited to a resin, metabolites, nucleosides, nucleotides, dmgs, toxins, transition state analogs, peptides, lipids, proteins, amino acids, nucleic acid molecules, hormones, carbohydrates, receptors, cells, viruses, bacteria and others.
  • non-nucleotide linker X is as defined herein.
  • non-nucleotide include either abasic nucleotide, polyether, polyamine, polyamide, peptide, carbohydrate, lipid, or polyhydrocarbon compounds. Specific examples include those described by Seela and Kaiser, Nucleic Acids Res. 1990, 7S:6353 and Nucleic Acids Res. 1987, 75:3113; Cload and Schepartz, J. Am. Chem. Soc. 1991, 773:6324; Richardson and Schepartz, J. Am. Chem. Soc. 1991, 773:5109; Ma et al, Nucleic Acids Res.
  • non-nucleotide further means any group or compound that can be incorporated into a nucleic acid chain in the place of one or more nucleotide units, including either sugar and/or phosphate substitutions, and allows the remaining bases to exhibit their enzymatic activity.
  • the group or compound can be abasic in that it does not contain a commonly recognized nucleotide base, such as adenosine, guanine, cytosine, uracil or thymine.
  • the invention features an enzymatic nucleic acid molecule having one or more non-nucleotide moieties, and having enzymatic activity to cleave an RNA or DNA molecule.
  • nucleic acid molecules that interact with target RNA molecules and down-regulate target genes e.g., prostaglandin D2 receptor (PTGDR), prostaglandin D2 synthetase (PTGDS), adenosine receptors (AR) such as adenosine receptor Al (ADORAl), A2a, A2b, and A3, NOGO-A, NOGO-B, NOGO-C, NI-35, NI-220, NI-250, myelin-associated glycoprotein, tenascin-R, NG-2 and/or their corresponding receptors, an DcappaB kinase (IKK) subunit and or protein kinase PKR gene) activity are expressed from transcription units
  • PGPDR prostaglandin D2 receptor
  • the recombinant vectors can be DNA plasmids or viral vectors.
  • Enzymatic nucleic acid molecule or antisense expressing viral vectors can be constmcted based on, but not limited to, adeno-associated vims, retrovirus, adenovims, or alphavims.
  • the recombinant vectors capable of expressing the enzymatic nucleic acid molecules or antisense can be delivered as described above, and persist in target cells.
  • viral vectors can be used that provide for transient expression of enzymatic nucleic acid molecules or antisense. Such vectors can be repeatedly administered as necessary.
  • the enzymatic nucleic acid molecules or antisense bind to the target RNA and down-regulate its function or expression. Delivery of enzymatic nucleic acid molecule or antisense expressing vectors can be systemic, such as by intravenous or intramuscular administration, by administration to target cells ex-planted from the patient followed by reintroduction into the patient, or by any other means that would allow for introduction into the desired target cell.
  • Antisense DNA can be expressed via the use of a single stranded DNA intracellular expression vector.
  • vectors any nucleic acid- and/or viral-based technique used to deliver a desired nucleic acid.
  • patient is meant an organism, which is a donor or recipient of explanted cells, or the cells themselves.
  • patient also refers to an organism to which the nucleic acid molecules of the invention can be administered.
  • a patient can be a mammal or mammalian cells. In one embodiment, a patient is a human or human cells.
  • enhanced enzymatic activity is meant to include activity measured in cells and/or in vivo where the activity is a reflection of both the catalytic activity and the stability of the nucleic acid molecules of the invention.
  • the product of these properties can be increased in vivo compared to an all RNA enzymatic nucleic acid or all DNA enzyme.
  • the activity or stability of the nucleic acid molecule can be decreased (i.e., less than ten- fold), but the overall activity ofthe nucleic acid molecule is enhanced, in vivo.
  • the nucleic acid molecules of the instant invention can be used to treat diseases or conditions discussed above.
  • a disease or condition associated with the levels of prostaglandin D2 receptor (PTGDR), prostaglandin D2 synthetase (PTGDS), adenosine receptors (AR) such as adenosine receptor Al (ADORAl), A2a, A2b, and A3, NOGO-A, NOGO-B, NOGO-C, NI- 35, NI-220, NI-250, myelin-associated glycoprotein, tenascin-R, NG-2 and/or their corresponding receptors, an DcappaB kinase (IKK) subunit and/or protein kinase PKR, the patient can be treated, or other appropriate cells can be treated, as is evident to those skilled in the art, individually or in combination with one or more drugs under conditions suitable for the treatment.
  • PPGDR prostaglandin D2 receptor
  • PSGDS prostaglandin D2 synth
  • the described molecules can be used in combination with other known treatments to treat conditions or diseases discussed above.
  • the described molecules can be used in combination with one or more known therapeutic agents to treat allergic diseases or conditions, including but not limited to asthma, allergic rhinitis, atopic dermatitis, and/or other allergic or inflammatory diseases and conditions which respond to the modulation of prostaglandin D2 receptor (PTGDR), prostaglandin D2 synthetase (PTGDS), adenosine receptors (AR) such as adenosine receptor Al (ADORAl), A2a, A2b, and A3, NOGO-A, NOGO-B, NOGO-C, NI-35, NI-220, NI-250, myelin-associated glycoprotein, tenascin-R, NG-2 and/or their corresponding receptors, an DcappaB kinase (IKK) subunit and/or
  • Figure 1 shows examples of chemically stabilized ribozyme motifs.
  • HH Rz represents hammerhead ribozyme motif (Usman et al, 1996, Curr. Op. Struct. Bio., 1, 527);
  • NCH Rz represents the NCH ribozyme motif (Ludwig & Sproat, International PCT Publication No. WO 98/58058);
  • G-Cleaver represents G-cleaver ribozyme motif (Kore et al, 1998, Nucleic Acids Research 26, 4116-4120, Eckstein et al, International PCT publication No. WO 99/16871).
  • N or n represent independently a nucleotide that can be same or different and have complementarity to each other; ri, represents ribo-Inosine nucleotide; arrow indicates the site of cleavage within the target.
  • Position 4 of the HH Rz and the NCH Rz is shown as having 2'-C-allyl modification, but those skilled in the art will recognize that this position can be modified with other modifications well known in the art, so long as such modifications do not significantly inhibit the activity ofthe ribozyme.
  • Figure 2 shows an example of the Amberzyme ribozyme motif that is chemically stabilized (see for example Beigelman et al, International PCT publication No. WO 99/55857).
  • Figure 3 shows an example of the Zinzyme A ribozyme motif that is chemically stabilized (see for example Beigelman et al, Beigelman et al, International PCT publication No. WO 99/55857).
  • Figure 4 shows an example of a specific DNAzyme motif, commonly referred to as the
  • Antisense molecules can be modified or unmodified RNA, DNA, or mixed polymer oligonucleotides and primarily function by specifically binding to matching sequences resulting in inhibition of peptide synthesis (Wu-Pong, Nov 1994, BioPharm, 20- 33).
  • the antisense oligonucleotide binds to target RNA by Watson Crick base-pairing and blocks gene expression by preventing ribosomal translation of the bound sequences either by steric blocking or by activating RNase H enzyme.
  • Antisense molecules can also alter protein synthesis by interfering with RNA processing or transport from the nucleus into the cytoplasm (Mukhopadhyay & Roth, 1996, Crit. Rev. in Oncogenesis 1, 151-190).
  • DNA chemistry which act as substrates for RNase H are phosphorothioates, phosphorodithioates, and borontrifluoridates. Recently it has been reported that 2'-arabino and 2 '-fluoro arabino- containing oligos can also activate RNase H activity.
  • antisense molecules have been described that utilize novel configurations of chemically modified nucleotides, secondary stmcture, and/or RNase H substrate domains
  • antisense deoxyoligoribonucleotides can be used to target RNA by means of DNA-RNA interactions, thereby activating RNase H, which digests the target RNA in the duplex.
  • Antisense DNA can be expressed via the use of a single stranded DNA intracellular expression vector or equivalents and variations thereof.
  • TFO Triplex Forming Oligonucleotides
  • 2-5A Antisense Chimera The 2-5A system is an interferon mediated mechanism for RNA degradation found in higher vertebrates (Mitra et al, 1996, Proc Nat Acad Sci USA 93, 6780-6785). Two types of enzymes, 2-5A synthetase and RNase L, are required for RNA cleavage. The 2-5A synthetases require double stranded RNA to form 2'-5' oligoadenylates (2-5 A). 2-5A then acts as an allosteric effector for utilizing RNase L, which has the ability to cleave single stranded RNA. The ability to form 2-5A stmctures with double stranded RNA makes this system particularly useful for inhibition of viral replication.
  • (2'-5') oligoadenylate stmctures can be covalently linked to antisense molecules to form chimeric oligonucleotides capable of RNA cleavage (Torrence, supra). These molecules putatively bind and activate a 2-5A dependent RNase, the oligonucleotide/enzyme complex then binds to a target RNA molecule which can then be cleaved by the RNase enzyme.
  • Nucleic acid aptamers can be selected to specifically bind to a particular ligand of interest (see for example Gold et al, US 5,567,588 and US 5,475,096, Gold et al, 1995, Annu. Rev. Biochem., 64, 763; Brody and Gold, 2000, J. Biotechnol, 14, 5; Sun, 2000, Curr. Opin. Mol. Ther., 2, 100; Kusser, 2000, J. Biotechnol, 74, 27; Hermann and Patel, 2000, Science, 287, 820; and Jayasena, 1999, Clinical Chemistry, 45, 1628).
  • nucleic acid aptamers with binding specificity for the NOGO receptor, prostaglandin D2 receptor (PTGDR), adenosine receptors (AR) such as adenosine receptor Al (ADORAl), A2a, A2b, and A3, NOGO-A, NOGO-B, NOGO-C, NI-35, NI-220, NI-250, myelin-associated glycoprotein, tenascin-R, NG-2 and/or their corresponding receptors.
  • Nucleic acid aptamers can include chemical modifications and linkers as described herein.
  • Aptamer molecules of the invention that bind to a cellular receptor such as prostaglandin D2 receptor (PTGDR), adenosine receptors (AR) such as adenosine receptor Al (ADORAl), A2a, A2b, and A3, NOGO-A, NOGO-B, NOGO-C, NI- 35, NI-220, NI-250, myelin-associated glycoprotein, tenascin-R, NG-2 and/or their corresponding receptors, or protein kinase PKR receptor, and modulate the activity of the receptor or ligand having specificity for the receptor.
  • PSGDR prostaglandin D2 receptor
  • AR adenosine receptors
  • ADORAl adenosine receptor Al
  • NOGO-A, NOGO-B, NOGO-C NI- 35, NI-220, NI-250, myelin-associated glycoprotein, tenascin-R, NG-2 and/or their
  • RNA interference refers to the process of sequence specific post transcriptional gene silencing in animals mediated by short interfering RNAs (siRNA) (Fire et al, 1998, Nature, 391, 806). The corresponding process in plants is commonly referred to as post transcriptional gene silencing or RNA silencing and is also referred to as quelling in fungi. The process of post transcriptional gene silencing is thought to be an evolutionarily conserved cellular defense mechanism used to prevent the expression of foreign genes which is commonly shared by diverse flora and phyla (Fire et al, 1999, Trends Genet., 15, 358).
  • Such protection from foreign gene expression may have evolved in response to the production of double stranded RNAs (dsRNA) derived from viral infection or the random integration of transposon elements into a host genome via a cellular response that specifically destroys homologous single stranded RNA or viral genomic RNA.
  • dsRNA double stranded RNAs
  • the presence of dsRNA in cells triggers the RNAi response though a mechanism that has yet to be fully characterized. This mechanism appears to be different from the interferon response that results from dsRNA mediated activation of protein kinase PKR and 2',5'-oligoadenylate synthetase resulting in non-specific cleavage of mRNA by ribonuclease L.
  • dsRNA ribonuclease rn enzyme
  • Dicer is involved in the processing of the dsRNA into short pieces of dsRNA known as short interfering RNAs (siRNA) (Berstein et al, 2001, Nature, 409, 363).
  • Short interfering RNAs derived from dicer activity are typically about 21-23 nucleotides in length and comprise about 19 base pair duplexes.
  • Dicer has also been implicated in the excision of 21 and 22 nucleotide small temporal RNAs (stRNA) from precursor RNA of conserved stmcture that are implicated in translational control (Hutvagner et al, 2001, Science, 293, 834).
  • the RNAi response also features an endonuclease complex containing a siRNA, commonly referred to as an RNA-induced silencing complex (RISC), which mediates cleavage of single stranded RNA having sequence homologous to the siRNA. Cleavage of the target RNA takes place in the middle of the region complementary to the guide sequence ofthe siRNA duplex (Elbashir et al, 2001, Genes Dev., 15, 188).
  • RISC RNA-induced silencing complex
  • RNAi mediated RNAi Short interfering RNA mediated RNAi has been studied in a variety of systems. Fire et al, 1998, Nature, 391, 806, were the first to observe RNAi in C. Elegans. Wianny and Goetz, 1999, Nature Cell Biol, 2, 70, describes RNAi mediated by dsRNA in mouse embryos. Hammond et al, 2000, Nature, 404, 293, describe RNAi in Drosophila cells transfected with dsRNA. Elbashir et al, 2001, Nature, 411, 494, describe RNAi induced by introduction of duplexes of synthetic 21 -nucleotide RNAs in cultured mammalian cells including human embryonic kidney and HeLa cells.
  • Enzymatic Nucleic Acid Several varieties of naturally-occurring enzymatic RNAs are presently known. In addition, several in vitro selection (evolution) strategies (Orgel, 1979, Proc. R. Soc. London, B 205, 435) have been used to evolve new nucleic acid catalysts capable of catalyzing cleavage and ligation of phosphodiester linkages (Joyce, 1989, Gene, 82, 83-87; Beaudry et al, 1992, Science 257, 635-641 ; Joyce, 1992, Scientific American 267, 90-97; Breaker et al, 1994, TIBTECH 12, 268; Bartel et ⁇ /., 1993, Science 261 :1411-1418; Szostak, 1993, T773S 17, 89-93; Kumar et al, 1995, FASEB J., 9, 1183; Breaker, 1996, Curr.
  • the enzymatic nature of an enzymatic nucleic acid molecule has significant advantages, one advantage being that the concentration of enzymatic nucleic acid molecule necessary to affect a therapeutic treatment is lower. This advantage reflects the ability of the enzymatic nucleic acid molecule to act enzymatically. Thus, a single enzymatic nucleic acid molecule is able to cleave many molecules of target RNA.
  • the enzymatic nucleic acid molecule is a highly specific inhibitor, with the specificity of inhibition depending not only on the base-pairing mechanism of binding to the target RNA, but also on the mechanism of target RNA cleavage. Single mismatches, or base-substitutions, near the site of cleavage can be chosen to completely eliminate catalytic activity of a enzymatic nucleic acid molecule.
  • Nucleic acid molecules having an endonuclease enzymatic activity are able to repeatedly cleave other separate RNA molecules in a nucleotide base sequence-specific manner. With the proper design, such enzymatic nucleic acid molecules can be targeted to
  • RNA transcripts and achieve efficient cleavage in vitro (Zaug et al, 324, Nature 429 1986;
  • trans-cleaving enzymatic nucleic acid molecules can be used as therapeutic agents for human disease (Usman & McSwiggen, 1995 Ann. Rep. Med. Chem. 30, 285-294; Christoffersen and Marr, 1995 J. Med. Chem. 38, 2023-2037).
  • Enzymatic nucleic acid molecules can be designed to cleave specific RNA targets within the background of cellular RNA. Such a cleavage event renders the RNA non-functional and abrogates protein expression from that RNA. In this manner, synthesis of a protein associated with a disease state can be selectively inhibited (Warashina et al, 1999, Chemistry and Biology, 6, 237-250).
  • Enzymatic nucleic acid molecules of the invention that are allosterically regulated can be used to down-regulate prostaglandin D2 receptor (PTGDR), prostaglandin D2 synthetase (PTGDS), adenosine receptors (AR) such as adenosine receptor Al (ADORAl), A2a, A2b, and A3, NOGO-A, NOGO-B, NOGO-C, NI-35, NI-220, NI-250, myelin-associated glycoprotein, tenascin-R, NG-2 and/or their corresponding receptors, an DcappaB kinase (IKK) subunit and/or protein kinase PKR expression.
  • PSGDR prostaglandin D2 receptor
  • PSGDS prostaglandin D2 synthetase
  • AR adenosine receptors
  • ADORAl adenosine receptor Al
  • A2a, A2b, and A3 NO
  • WO 99/29842 are designed to respond to a signaling agent, for example, mutant and/or wild type protein, other proteins and/or RNAs involved in target gene signal transduction, compounds, metals, polymers, molecules and/or dmgs that are targeted to target gene expressing cells etc., which in turn modulates the activity of the enzymatic nucleic acid molecule.
  • a signaling agent for example, mutant and/or wild type protein, other proteins and/or RNAs involved in target gene signal transduction, compounds, metals, polymers, molecules and/or dmgs that are targeted to target gene expressing cells etc.
  • the allosteric enzymatic nucleic acid molecule's activity is activated or inhibited such that the expression of a particular target is selectively down-regulated.
  • the target can comprise wild-type protein, mutant protein, and/or a predetermined component of the protein's signal transduction pathway.
  • allosteric enzymatic nucleic acid molecules that are activated by interaction with a RNA encoding a PTGDR protein are used as therapeutic agents in vivo.
  • the presence of RNA encoding the PTGDS protein activates the allosteric enzymatic nucleic acid molecule that subsequently cleaves the RNA encoding a PTGDR protein resulting in the inhibition of PTGDR protein expression. In this manner, cells that express both PTGDS and PTGDR protein are selectively targeted.
  • an allozyme can be activated by a prostaglandin D2 receptor (PTGDR), prostaglandin D2 synthetase (PTGDS), adenosine receptors (AR) such as adenosine receptor Al (ADORAl), A2a, A2b, and A3, NOGO-A, NOGO-B, NOGO-C, NI- 35, NI-220, NI-250, myelin-associated glycoprotein, tenascin-R, NG-2 and/or their corresponding receptors, an DcappaB kinase (IKK) subunit and/or protein kinase PKR protein, peptide, or mutant polypeptide that causes the allozyme to inhibit the expression of a target gene, by, for example, cleaving RNA encoded by the target gene.
  • PGPDR prostaglandin D2 receptor
  • PSGDS prostaglandin D2 synthetase
  • AR adenosine receptors
  • the allozyme acts as a decoy to inhibit the function of the target protein and also inhibit the expression of the protein once activated by the prostaglandin D2 receptor (PTGDR), prostaglandin D2 synthetase (PTGDS), adenosine receptors (AR) such as adenosine receptor Al (ADORAl), A2a, A2b, and A3, NOGO-A, NOGO-B, NOGO-C, NI- 35, NI-220, NI-250, myelin-associated glycoprotein, tenascin-R, NG-2 and/or their corresponding receptors, an DcappaB kinase (IKK) subunit and/or protein kinase PKR protein.
  • PSGDR prostaglandin D2 receptor
  • PSGDS prostaglandin D2 synthetase
  • AR adenosine receptors
  • ADORAl adenosine receptor Al
  • Targets for useful enzymatic nucleic acid molecules and antisense nucleic acids can be determined as disclosed in Draper et al, WO 93/23569; Sullivan et al, WO 93/23057; Thompson et al, WO 94/02595; Draper et al, WO 95/04818; McSwiggen et al, US Patent No. 5,525,468, and hereby inco ⁇ orated by reference herein in totality.
  • Other examples include the following PCT applications, which concern inactivation of expression of disease- related genes: WO 95/23225, WO 95/13380, WO 94/02595, inco ⁇ orated by reference herein.
  • Enzymatic nucleic acid molecules and antisense to such targets are designed as described in those applications and synthesized to be tested in vitro and in vivo, as also described.
  • prostaglandin D2 receptor PSGDR
  • prostaglandin D2 synthetase PSGDS
  • adenosine receptors AR
  • ADORAl adenosine receptor Al
  • A2a, A2b, and A3 NOGO-A, NOGO-B, NOGO-C, NI-35, NI-220, NI-250, myelin-associated glycoprotein, tenascin-R, NG-2 and/or their corresponding receptors
  • Antisense, hammerhead, DNAzyme, NCH, amberzyme, zinzyme, or G-Cleaver enzymatic nucleic acid molecule binding/cleavage sites were identified. These sites are shown in Tables III to XXIII (all sequences are 5' to 3' in the tables; underlined regions can be any sequence "X" or linker X, the actual sequence is not relevant here).
  • the nucleotide base position is noted in the Tables as that site to be cleaved by the designated type of enzymatic nucleic acid molecule.
  • mouse targeted enzymatic nucleic acid molecules can be useful to test efficacy of action of the enzymatic nucleic acid molecule and/or antisense prior to testing in humans.
  • Antisense, siRNA, hammerhead, DNAzyme, NCH, amberzyme, zinzyme or G-Cleaver enzymatic nucleic acid molecule binding/cleavage sites were identified.
  • the nucleic acid molecules are individually analyzed by computer folding (Jaeger et al, 1989 Proc. Natl. Acad. Sci.
  • binding arm lengths can be chosen to optimize activity.
  • Antisense, siRNA, hammerhead, DNAzyme, NCH, amberzyme, zinzyme or G-Cleaver enzymatic nucleic acid molecule binding/cleavage sites were identified and were designed to anneal to various sites in the RNA target.
  • the binding arms are complementary to the target site sequences described above.
  • the nucleic acid molecules were chemically synthesized. The method of synthesis used follows the procedure for normal DNA/RNA synthesis as described below and in Usman et al, 1987 J. Am. Chem. Soc, 109, 7845; Scaringe et al, 1990 Nucleic Acids Res., 18, 5433; and Wincott et al, 1995 Nucleic Acids Res. 23, 2677- 2684; Caruthers et al, 1992, Methods in Enzymology 211,3-19.
  • nucleic acids greater than 100 nucleotides in length is difficult using automated methods, and the therapeutic cost of such molecules is prohibitive.
  • small nucleic acid motifs small refers to nucleic acid motifs less than about 100 nucleotides in length, and in one embodiment less than about 80 nucleotides in length, and in another embodiment less than about 50 nucleotides in length; e.g., antisense oligonucleotides, hammerhead or the NCH ribozymes
  • the simple stmcture of these molecules increases the ability of the nucleic acid to invade targeted regions of RNA stmcture.
  • Exemplary molecules of the instant invention are chemically synthesized, and others can similarly be synthesized.
  • Oligonucleotides are synthesized using protocols known in the art as described in Camthers et al, 1992, Methods in Enzymology 211, 3-19, Thompson et al, International PCT Publication No. WO 99/54459, Wincott et al, 1995, Nucleic Acids Res. 23, 2677-2684, Wincott et al, 1997, Methods Mol. Bio., 74, 59, Brennan et al, 1998, Biotechnol Bioeng., 61, 33-45, and Brennan, US patent No. 6,001,311. All of these references are inco ⁇ orated herein by reference.
  • oligonucleotides makes use of common nucleic acid protecting and coupling groups, such as dimethoxytrityl at the 5'-end, and phosphoramidites at the 3'-end.
  • small scale syntheses are conducted on a 394 Applied Biosystems, Inc. synthesizer using a 0.2 ⁇ mol scale protocol with a 2.5 min coupling step for 2'-O-methylated nucleotides and a 45 sec coupling step for 2'-deoxy nucleotides.
  • Table II outlines the amounts and the contact times of the reagents used in the synthesis cycle.
  • syntheses at the 0.2 ⁇ mol scale can be performed on a 96-well plate synthesizer, such as the instmment produced by Protogene (Palo Alto, CA) with minimal modification to the cycle.
  • synthesizer include; detritylation solution is 3% TCA in methylene chloride (ABI); capping is performed with 16% N-methyl imidazole in THF (ABI) and 10% acetic anhydride/10% 2,6-lutidine in THF (ABI); and oxidation solution is 16.9 mM h, 49 mM pyridine, 9% water in THF (PERSEPTIVETM). Burdick & Jackson Synthesis Grade acetonitrile is used directly from the reagent bottle. S- Ethyltetrazole solution (0.25 M in acetonitrile) is made up from the solid obtained from American International Chemical, Inc. Alternately, for the introduction of phosphorothioate linkages, Beaucage reagent (3H-l,2-Benzodithiol-3-one 1,1-dioxide, 0.05 M in acetonitrile) is used.
  • Deprotection of the antisense oligonucleotides is performed as follows: the polymer- bound trityl-on oligoribonucleotide is transferred to a 4 mL glass screw top vial and suspended in a solution of 40% aq. methylamine (1 mL) at 65 °C for 10 min. After cooling to -20 °C, the supernatant is removed from the polymer support. The support is washed three times with 1.0 mL of EtOH:MeC ⁇ :H2O/3:l :l, vortexed and the supernatant is then added to the first supernatant. The combined supematants, containing the oligoribonucleotide, are dried to a white powder.
  • RNA including certain enzymatic nucleic acid molecules follows the procedure as described in Usman et al, 1987, J. Am. Chem. Soc, 109, 7845; Scaringe et al, 1990, Nucleic Acids Res., 18, 5433; and Wincott et al, 1995, Nucleic Acids Res. 23, 2677-2684 Wincott et al, 1997, Methods Mol. Bio., 74, 59, and makes use of common nucleic acid protecting and coupling groups, such as dimethoxytrityl at the 5 '-end, and phosphoramidites at the 3'-end.
  • common nucleic acid protecting and coupling groups such as dimethoxytrityl at the 5 '-end, and phosphoramidites at the 3'-end.
  • small scale syntheses are conducted on a 394 Applied Biosystems, Inc. synthesizer using a 0.2 ⁇ mol scale protocol with a 7.5 min coupling step for alkylsilyl protected nucleotides and a 2.5 min coupling step for 2'-O-methylated nucleotides.
  • Table II outlines the amounts and the contact times of the reagents used in the synthesis cycle.
  • syntheses at the 0.2 ⁇ mol scale can be done on a 96-well plate synthesizer, such as the instmment produced by Protogene (Palo Alto, CA) with minimal modification to the cycle.
  • Average coupling yields on the 394 Applied Biosystems, Inc. synthesizer, determined by colorimetric quantitation of the trityl fractions, are typically 91.5-99%.
  • synthesizer include; detritylation solution is 3%> TCA in methylene chloride (ABI); capping is performed with 16% N-methyl imidazole in THF (ABI) and 10% acetic anhydride/10% 2,6-lutidine in THF (ABI); oxidation solution is 16.9 mM I 2 , 49 mM pyridine, 9% water in THF
  • Deprotection of the R ⁇ A is performed using either a two-pot or one-pot protocol.
  • the polymer-bound trityl-on oligoribonucleotide is transferred to a 4 mL glass screw top vial and suspended in a solution of 40% aq. methylamine (1 mL) at 65 °C for 10 min. After cooling to -20 °C, the supernatant is removed from the polymer support. The support is washed three times with 1.0 mL of EtOH:MeC ⁇ :H2O/3:l:l, vortexed and the supernatant is then added to the first supernatant.
  • the combined supematants, containing the oligoribonucleotide, are dried to a white powder.
  • the base deprotected oligoribonucleotide is resuspended in anhydrous TEA/HF/NMP solution (300 ⁇ L of a solution of 1.5 mL N- methylpyrrolidinone, 750 ⁇ L TEA and 1 mL TEA » 3HF to provide a 1.4 M HF concentration) and heated to 65 °C. After 1.5 h, the oligomer is quenched with 1.5 M NH4HCO3.
  • the polymer-bound trityl-on oligoribonucleotide is transferred to a 4 mL glass screw top vial and suspended in a solution of 33% ethanolic methylamine/DMSO: 1/1 (0.8 mL) at 65 °C for 15 min.
  • the vial is brought to r.t. TEA ⁇ HF
  • the quenched NH 4 HCO3 solution is loaded onto a C-18 containing cartridge that had been prewashed with acetonitrile followed by 50 mM TEAA. After washing, the loaded cartridge with water, the RNA is detritylated with
  • Inactive hammerhead ribozymes or binding attenuated control (BAC) oligonucleotides are synthesized by substituting a U for G5 and a U for A14 (numbering from Hertel, K. J., et al, 1992, Nucleic Acids Res., 20, 3252). Similarly, one or more nucleotide substitutions can be introduced in other enzymatic nucleic acid molecules to inactivate the molecule and such molecules can serve as a negative control.
  • nucleic acid molecules of the present invention can be synthesized separately and joined together post-synthetically, for example by ligation (Moore et al, 1992, Science 256, 9923; Draper et al, International PCT publication No. WO 93/23569;
  • nucleic acid molecules of the present invention can be modified extensively to enhance stability by modification with nuclease resistant groups, for example, 2'-amino, 2'-C- allyl, 2'-flouro, 2'-O-methyl, 2'-H (for a review see Usman and Cedergren, 1992, TIBS 17, 34; Usman et al, 1994, Nucleic Acids Symp. Ser. 31, 163).
  • Ribozymes are purified by gel electrophoresis using general methods or are purified by high pressure liquid chromatography (HPLC; See Wincott et al, Supra, the totality of which is hereby inco ⁇ orated herein by reference) and are re-suspended in water.
  • sequences of the nucleic acid molecules including enzymatic nucleic acid molecules and antisense, that are chemically synthesized, are shown in Tables III-XXIII.
  • sequences of the enzymatic nucleic acid constmcts that are chemically synthesized are complementary to the Substrate sequences shown in Tables III-XXIII.
  • Those in the art will recognize that these sequences are representative only of many more such sequences where the enzymatic portion of the enzymatic nucleic acid (all but the binding arms) is altered to affect activity.
  • the enzymatic nucleic acid constmct sequences listed in Tables III-XXIII can be formed of ribonucleotides or other nucleotides or non-nucleotides. Such enzymatic nucleic acid molecules with enzymatic activity are equivalent to the enzymatic nucleic acid molecules described specifically in the Tables. Optimizing Activity ofthe nucleic acid molecule ofthe invention.
  • oligonucleotides are modified to enhance stability and/or enhance biological activity by modification with nuclease resistant groups, for example, 2'-amino, 2'-C-allyl, 2'-flouro, 2'-O-methyl, 2'-H, nucleotide base modifications (for a review see Usman and Cedergren, 1992, 775S. 17, 34; Usman et al, 1994, Nucleic Acids Symp. Ser. 31, 163; Burgin et al, 1996, Biochemistry, 35, 14090).
  • nuclease resistant groups for example, 2'-amino, 2'-C-allyl, 2'-flouro, 2'-O-methyl, 2'-H, nucleotide base modifications
  • Nucleic acid molecules having chemical modifications that maintain or enhance activity are provided. Such a nucleic acid is also generally more resistant to nucleases than an unmodified nucleic acid. Thus, in a cell and/or in vivo the activity may not be significantly lowered.
  • Therapeutic nucleic acid molecules delivered exogenously are optimally stable within cells until translation of the target RNA has been inhibited long enough to reduce the levels ofthe undesirable protein. This period of time varies between hours to days depending upon the disease state.
  • nucleic acid molecules must be resistant to nucleases in order to function as effective intracellular therapeutic agents. Improvements in the chemical synthesis of RNA and DNA (Wincott et al, 1995 Nucleic Acids Res.
  • nucleic acid molecules of the invention include one or more G- clamp nucleotides.
  • a G-clamp nucleotide is a modified cytosine analog wherein modifications result in the ability to hydrogen bond both Watson-Crick and Hoogsteen faces of a complementary guanine within a duplex, see for example Lin and Matteucci, 1998, J. Am. Chem. Soc, 120, 8531-8532.
  • a single G-clamp analog substation within an oligonucleotide can result in substantially enhanced helical thermal stability and mismatch discrimination when hybridized to complementary oligonucleotides.
  • the inclusion of such nucleotides in nucleic acid molecules of the invention can enable both enhanced affinity and specificity to nucleic acid targets.
  • nucleic acid molecules ⁇ e.g., enzymatic nucleic acid molecules and antisense nucleic acid molecules
  • delivered exogenously are optimally stable within cells until translation of the target RNA has been inhibited long enough to reduce the levels of the undesirable protein. This period of time varies between hours to days depending upon the disease state.
  • These nucleic acid molecules should be resistant to nucleases in order to function as effective intracellular therapeutic agents. Improvements in the chemical synthesis of nucleic acid molecules described in the instant invention and in the art have expanded the ability to modify nucleic acid molecules by introducing nucleotide modifications to enhance their nuclease stability as described above.
  • the invention features conjugates and/or complexes of nucleic acid molecules targeting prostaglandin D2 receptor (PTGDR), prostaglandin D2 synthetase (PTGDS), adenosine receptors (AR) such as adenosine receptor Al (ADORAl), A2a, A2b, and A3, NOGO-A, NOGO-B, NOGO-C, NI-35, NI-220, NI-250, myelin-associated glycoprotein, tenascin-R, NG-2 and/or their corresponding receptors, an DcappaB kinase (IKK) subunit and/or protein kinase PKR.
  • PAGDR prostaglandin D2 receptor
  • PSGDS prostaglandin D2 synthetase
  • AR adenosine receptors
  • ADORAl adenosine receptor Al
  • A2a, A2b, and A3 NOGO-A, NOGO-B, NOGO
  • compositions and conjugates are used to facilitate delivery of molecules into a biological system, such as cells.
  • the conjugates provided by the instant invention can impart therapeutic activity by transferring therapeutic compounds across cellular membranes, altering the pharmacokinetics, and/or modulating the localization of nucleic acid molecules of the invention.
  • the present invention encompasses the design and synthesis of novel agents for the delivery of molecules, including but not limited to small molecules, lipids, phospholipids, nucleosides, nucleotides, nucleic acids, antibodies, toxins, negatively charged polymers and other polymers, for example proteins, peptides, hormones, carbohydrates, polyethylene glycols, or polyamines, across cellular membranes.
  • the transporters described are designed to be used either individually or as part of a multi- component system, with or without degradable linkers. These compounds are expected to improve delivery and/or localization of nucleic acid molecules of the invention into a number of cell types originating from different tissues, in the presence or absence of semm (see Sullenger and Cech, US 5,854,038). Conjugates of the molecules described herein can be attached to biologically active molecules via linkers that are biodegradable, such as biodegradable nucleic acid linker molecules.
  • biodegradable nucleic acid linker molecule refers to a nucleic acid molecule that is designed as a biodegradable linker to connect one molecule to another molecule, for example, a biologically active molecule.
  • the stability of the biodegradable nucleic acid linker molecule can be modulated by using various combinations of ribonucleotides, deoxyribonucleotides, and chemically modified nucleotides, for example 2'-O-methyl, 2'-fluoro, 2'-amino, 2'-O-amino, 2'-C-allyl, 2'-O-allyl, and other 2'-modified or base modified nucleotides.
  • the biodegradable nucleic acid linker molecule can be a dimer, trimer, tetramer or longer nucleic acid molecule, for example an oligonucleotide of about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 nucleotides in length, or can comprise a single nucleotide with a phosphoms based linkage, for example a phosphoramidate or phosphodiester linkage.
  • the biodegradable nucleic acid linker molecule can also comprise nucleic acid backbone, nucleic acid sugar, or nucleic acid base modifications.
  • biodegradable refers to degradation in a biological system, for example enzymatic degradation or chemical degradation.
  • biologically active molecule refers to compounds or molecules that are capable of eliciting or modifying a biological response in a system.
  • Non- limiting examples of biologically active molecules contemplated by the instant invention include therapeutically active molecules such as antibodies, hormones, antivirals, peptides, proteins, chemotherapeutics, small molecules, vitamins, co-factors, nucleosides, nucleotides, oligonucleotides, enzymatic nucleic acids, antisense nucleic acids, triplex forming oligonucleotides, 2,5-A chimeras, siRNA, dsRNA, allozymes, aptamers, decoys and analogs thereof.
  • therapeutically active molecules such as antibodies, hormones, antivirals, peptides, proteins, chemotherapeutics, small molecules, vitamins, co-factors, nucleosides, nucleotides, oligonucleotides, enzymatic nucleic acids, antisense nucleic acids, triplex forming oligonucleotides, 2,5-A chimeras, siRNA, dsRNA, all
  • Biologically active molecules of the invention also include molecules capable of modulating the pharmacokinetics and/or pharmacodynamics of other biologically active molecules, for example lipids and polymers such as polyamines, polyamides, polyethylene glycol and other polyethers.
  • lipids and polymers such as polyamines, polyamides, polyethylene glycol and other polyethers.
  • phospholipid refers to a hydrophobic molecule comprising at least one phosphoms group.
  • a phospholipid can comprise a phosphoms containing group and saturated or unsaturated alkyl group, optionally substituted with OH, COOH, oxo, amine, or substituted or unsubstituted aryl groups.
  • nucleic acid catalysts having chemical modifications that maintain or enhance enzymatic activity are provided.
  • Such nucleic acids are also generally more resistant to nucleases than unmodified nucleic acids.
  • the activity of the nucleic acid may not be significantly lowered.
  • enzymatic nucleic acids are useful in a cell and/or in vivo even if activity over all is reduced 10 fold (Burgin et al, 1996, Biochemistry, 35, 14090).
  • Such enzymatic nucleic acids herein are said to "maintain" the enzymatic activity of an all RNA ribozyme or all DNA DNAzyme.
  • nucleic acid molecules comprise a 5' and/or a 3'- cap stmcture.
  • cap stmcture is meant chemical modifications, which have been inco ⁇ orated at either terminus of the oligonucleotide (see for example Wincott et al, WO 97/26270, inco ⁇ orated by reference herein). These terminal modifications protect the nucleic acid molecule from exonuclease degradation, and can help in delivery and/or localization within a cell.
  • the cap can be present at the 5 '-terminus (5 '-cap) or at the 3 '-terminus (3 '-cap) or can be present on both terminus.
  • the 5 '-cap includes inverted abasic residue (moiety), 4',5'-methylene nucleotide; l-(beta-D-erythrofuranosyl) nucleotide, 4'-thio nucleotide, carbocyclic nucleotide; 1,5-anhydrohexitol nucleotide; L-nucleo tides; alpha- nucleotides; modified base nucleotide; phosphorodithioate linkage; tbreo-pentofuranosyl nucleotide; acyclic 3',4'-seco nucleotide; acyclic 3,4-dihydroxybutyl nucleotide; acyclic 3,5- dihydroxypentyl nucleotide, 3 '-3 '-inverted nucleotide moiety; 3'-3'-inverted abasic moiety; 3'- 2'-inverted nucleotide moiety
  • the 3 '-cap includes, for example 4', 5 '-methylene nucleotide; 1- (beta-D-erythrofuranosyl) nucleotide; 4'-thio nucleotide, carbocyclic nucleotide; 5'-amino- alkyl phosphate; l,3-diamino-2-propyl phosphate, 3-aminopropyl phosphate; 6-aminohexyl phosphate; 1,2-aminododecyl phosphate; hydroxypropyl phosphate; 1,5-anhydrohexitol nucleotide; L-nucleotide; alpha-nucleotide; modified base nucleotide; phosphorodithioate; tbreo-pentofuranosyl nucleotide; acyclic 3',4'-seco nucleotide; 3,4-dihydroxybutyl nucleotide; 3,5-
  • non-nucleotide any group or compound that can be inco ⁇ orated into a nucleic acid chain in the place of one or more nucleotide units, including either sugar and/or phosphate substitutions, and allows the remaining bases to exhibit their enzymatic activity.
  • the group or compound is abasic in that it does not contain a commonly recognized nucleotide base, such as adenosine, guanine, cytosine, uracil or thymine.
  • alkyl refers to a saturated aliphatic hydrocarbon, including straight-chain, branched-chain, and cyclic alkyl groups.
  • the alkyl group can have, for example, 1 to 12 carbons. In one embodiment of the invention, the alkyl group is a lower alkyl of from 1 to 7 carbons. In another embodiment the alkyl group is 1 to 4 carbons.
  • alkenyl groups which are unsaturated hydrocarbon groups containing at least one carbon-carbon double bond, including straight-chain, branched-chain, and cyclic groups.
  • the alkenyl group can have, for example, 1 to 12 carbons.
  • the alkenyl group can be a lower alkenyl of from 1 to 7 carbons.
  • the alkenyl group can be 1 to 4 carbons.
  • alkyl also includes alkynyl groups which have an unsaturated hydrocarbon group containing at least one carbon-carbon triple bond, including straight-chain, branched-chain, and cyclic groups.
  • the alkynyl group can have, for example, 1 to 12 carbons.
  • the alkynyl group is a lower alkynyl of from 1 to 7 carbons.
  • the alkynyl group is 1 to 4 carbons.
  • alkyl groups can also include aryl, alkylaryl, carbocyclic aryl, heterocyclic aryl, amide and ester groups.
  • An "aryl” group refers to an aromatic group which has at least one ring having a conjugated p electron system and includes carbocyclic aryl, heterocyclic aryl and biaryl groups, all of which can be optionally substituted.
  • the preferred substituent(s) of aryl groups are halogen, trihalomethyl, hydroxyl, SH, OH, cyano, alkoxy, alkyl, alkenyl, alkynyl, and amino groups.
  • alkylaryl refers to an alkyl group (as described above) covalently joined to an aryl group (as described above).
  • Carbocyclic aryl groups are groups wherein the ring atoms on the aromatic ring are all carbon atoms. The carbon atoms are optionally substituted.
  • Heterocyclic aryl groups are groups having from 1 to 3 heteroatoms as ring atoms in the aromatic ring and the remainder ofthe ring atoms are carbon atoms.
  • Suitable heteroatoms include oxygen, sulfur, and nitrogen, and include furanyl, thienyl, pyridyl, pyrrolyl, N-lower alkyl pyrrolo, pyrimidyl, pyrazinyl, imidazolyl and the like, all optionally substituted.
  • An "amide” refers to an -C(O)-NH-R, where R is either alkyl, aryl, alkylaryl or hydrogen.
  • An “ester” refers to an -C(O)-OR', where R is either alkyl, aryl, alkylaryl or hydrogen.
  • nucleotide is meant a heterocyclic nitrogenous base in N-glycosidic linkage with a phosphorylated sugar.
  • Nucleotides are recognized in the art to include natural bases (standard), and modified bases well known in the art. Such bases are generally located at the 1' position of a nucleotide sugar moiety. Nucleotides generally comprise a base, sugar and a phosphate group.
  • the nucleotides can be unmodified or modified at the sugar, phosphate and/or base moiety, (also referred to interchangeably as nucleotide analogs, modified nucleotides, non-natural nucleotides, non-standard nucleotides and other; see for example, Usman and McSwiggen, supra; Eckstein et al, International PCT Publication No. WO 92/07065; Usman et al, International PCT Publication No. WO 93/15187; Uhlman & Peyman, supra all are hereby inco ⁇ orated by reference herein).
  • modified nucleic acid bases known in the art as summarized by Limbach et al, 1994, Nucleic Acids Res. 22, 2183.
  • nucleic acids include, for example, inosine, purine, pyridin-4-one, pyridin-2-one, phenyl, pseudouracil, 2, 4, 6-trimethoxy benzene, 3-methyl uracil, dihydrouridine, naphthyl, aminophenyl, 5-alkylcytidines (e.g., 5-methylcytidine), 5-alkyluridines (e.g., ribothymidine), 5-halouridine (e.g., 5-bromouridine) or 6-azapyrimidines or 6-alkylpyrimidines (e.g.
  • 6-methyluridine 6-methyluridine
  • propyne quesosine, 2- thiouridine, 4-thiouridine, wybutosine, wybutoxosine, 4-acetylcytidine, 5- (carboxyhydroxymethyl)uridine, 5 '-carboxymethylaminomethyl-2-thiouridine, 5- carboxymethylaminomethyluridine, beta-D-galactosylqueosine, 1-methyladenosine, 1- methylinosine, 2,2-dimethylguanosine, 3-methylcytidine, 2-methyladenosine, 2- methylguanosine, N6-methyladenosine, 7-methylguanosine, 5-methoxyaminomethyl-2- thiouridine, 5-methylaminomethyluridine, 5-methylcarbonylmethyluridine, 5- methyloxyuridine, 5-methyl-2-thiouridine, 2-methylthio-N6-isopentenyladenosine, beta-D- mannosylque
  • modified bases in this aspect is meant nucleotide bases other than adenine, guanine, cytosine and uracil at 1' position or their equivalents; such bases can be used at any position, for example, within the catalytic core of an enzymatic nucleic acid molecule and/or in the substrate-binding regions ofthe nucleic acid molecule.
  • nucleoside is meant a heterocyclic nitrogenous base in N-glycosidic linkage with a sugar.
  • Nucleosides are recognized in the art to include natural bases (standard), and modified bases well known in the art. Such bases are generally located at the 1' position of a nucleoside sugar moiety.
  • Nucleosides generally comprise a base and sugar group.
  • the nucleosides can be unmodified or modified at the sugar, and/or base moiety, (also referred to interchangeably as nucleoside analogs, modified nucleosides, non-natural nucleosides, non- standard nucleosides and other; see for example, Usman and McSwiggen, supra; Eckstein et al, International PCT Publication No.
  • nucleic acids Some of the non- limiting examples of chemically modified and other natural nucleic acid bases that can be introduced into nucleic acids include, inosine, purine, pyridin-4-one, pyridin-2-one, phenyl, pseudouracil, 2, 4, 6-trimethoxy benzene, 3-methyl uracil, dihydrouridine, naphthyl, aminophenyl, 5-alkylcytidines (e.g., 5-methylcytidine), 5-alkyluridines (e.g., ribothymidine), 5-halouridine (e.g., 5 -bromo uridine) or 6-azapyrimidines or 6-alkylpyrimidines (e.g.
  • modified bases in this aspect is meant nucleoside bases other than adenine, guanine, cytosine and uracil at 1' position or their equivalents; such bases can be used at any position, for example, within the catalytic core of an enzymatic nucleic acid molecule and/or in the substrate-binding regions ofthe nucleic acid molecule.
  • the invention features modified enzymatic nucleic acid molecules with phosphate backbone modifications comprising one or more phosphorothioate, phosphorodithioate, methylphosphonate, mo ⁇ holino, amidate carbamate, carboxymethyl, acetamidate, polyamide, sulfonate, sulfonamide, sulfamate, formacetal, thioformacetal, and/or alkylsilyl, substitutions.
  • abasic sugar moieties lacking a base or having other chemical groups in place of a base at the 1' position, for example a 3 ',3 '-linked or 5 ',5 '-linked deoxyabasic ribose derivative (for more details see Wincott et al, International PCT publication No. WO 97/26270).
  • unmodified nucleoside is meant one of the bases adenine, cytosine, guanine, thymine, uracil joined to the 1' carbon of ⁇ -D-ribo-furanose.
  • modified nucleoside any nucleotide base that contains a modification in the chemical stmcture of an unmodified nucleotide base, sugar and/or phosphate.
  • amino is meant 2'-NH 2 or 2'-O- NH 2 , which can be modified or unmodified. Such modified groups are described, for example, in Eckstein et al, U.S. Patent 5,672,695 and Matulic-Adamic et al, W ⁇ 98/28317, respectively, which are both inco ⁇ orated by reference in their entireties.
  • nucleic acid e.g., antisense and ribozyme
  • modifications to nucleic acid can be made to enhance the utility of these molecules.
  • modifications can enhance shelf-life, half-life in vitro, stability, and ease of introduction of such oligonucleotides to the target site, including e.g., enhancing penetration of cellular membranes and conferring the ability to recognize and bind to targeted cells.
  • nucleic acid-based molecules of the invention can lead to better treatment of the disease progression by affording the possibility of combination therapies (e.g., multiple enzymatic nucleic acid molecules targeted to different genes, enzymatic nucleic acid molecules coupled with known small molecule inhibitors, or intermittent treatment with combinations of enzymatic nucleic acid molecules (including different enzymatic nucleic acid molecule motifs) and/or other chemical or biological molecules).
  • combination therapies e.g., multiple enzymatic nucleic acid molecules targeted to different genes, enzymatic nucleic acid molecules coupled with known small molecule inhibitors, or intermittent treatment with combinations of enzymatic nucleic acid molecules (including different enzymatic nucleic acid molecule motifs) and/or other chemical or biological molecules).
  • the treatment of patients with nucleic acid molecules can also include combinations of different types of nucleic acid molecules.
  • Therapies can be devised which include a mixture of enzymatic nucleic acid molecules (including different enzymatic nucleic acid molecule motifs), antisense and/or 2- 5 A chimera molecules to one or more targets to alleviate symptoms of a disease.
  • nucleic acid molecules Methods for the delivery of nucleic acid molecules are described in Akhtar et al, 1992, Trends Cell Bio., 2, 139; and Delivery Strategies for Antisense Oligonucleotide Therapeutics, ed. Akhtar, 1995 which are both inco ⁇ orated herein by reference.
  • Sullivan et al, PCT WO 94/02595 further describes the general methods for delivery of enzymatic RNA molecules. These protocols can be utilized for the delivery of virtually any nucleic acid molecule.
  • Nucleic acid molecules can be administered to cells by a variety of methods known to those familiar to the art, including, but not restricted to, encapsulation in liposomes, by iontophoresis, or by inco ⁇ oration into other vehicles, such as hydrogels, cyclodextrins, biodegradable nanocapsules, and bioadhesive microspheres.
  • the nucleic acid molecules or the invention are administered via pulmonary delivery, such as by inhalation of an aerosol or spray dried formulation administered by an inhalation device or nebulizer.
  • the nucleic acid/vehicle combination is locally delivered by direct injection or by use of an infusion pump.
  • routes of delivery include, but are not limited to oral (tablet or pill form) and/or intrathecal delivery (Gold, 1997, Neuroscience, 76, 1153-1158).
  • Other approaches include the use of various transport and carrier systems, for example though the use of conjugates and biodegradable polymers.
  • dmg delivery strategies including CNS delivery, see Ho et al, 1999, Curr. Opin. Mol. Ther., 1, 336-343 and Jain, Drug Delivery Systems: Technologies and Commercial Opportunities, Decision Resources, 1998 and Groothuis et al, 1997, J. NeuroVirol, 3, 387-400.
  • nucleic acid delivery and administration More detailed descriptions of nucleic acid delivery and administration are provided in Sullivan et al, supra, Draper et al, PCT WO93/23569, Beigelman et al, PCT WO99/05094, and Klimuk et al, PCT WO99/04819 all of which have been inco ⁇ orated by reference herein.
  • Epa et al, 2000, Antisense Nuc. Acid Drug Dev., 10, 469 describe an in vivo mouse study in which beta-cyclodextrin-adamantane-oligonucleotide conjugates were used to target the p75 neurotrophin receptor in neuronally differentiated PC 12 cells. Following a two week course of IP administration, pronounced uptake of p75 neurotrophin receptor antisense was observed in dorsal root ganglion (DRG) cells. In addition, a marked and consistent down-regulation of p75 was observed in DRG neurons. Additional approaches to the targeting of nucleic acid to neurons are described in Broaddus et al, 1998, J.
  • Nucleic acid molecules of the invention are therefore amenable to delivery to and uptake by cells that express NOGO and NOGO receptors for modulation of NOGO and/or NOGO receptor expression.
  • nucleic acid molecules of the invention targeting NOGO and NOGO receptors is provided by a variety of different strategies.
  • Traditional approaches to CNS delivery include, but are not limited to, intrathecal and intracerebroventricular administration, implantation of catheters and pumps, direct injection or perfusion at the site of injury or lesion, injection into the brain arterial system, or by chemical or osmotic opening ofthe blood-brain barrier.
  • Other approaches can include the use of various transport and carrier systems, for example though the use of conjugates and biodegradable polymers.
  • gene therapy approaches for example as described in Kaplitt et al, US 6,180,613, can be used to express nucleic acid molecules in the CNS.
  • the molecules of the instant invention can be used as pharmaceutical agents.
  • Pharmaceutical agents prevent, inhibit the occurrence, or treat (alleviate a symptom to some extent, or all ofthe symptoms) of a disease state in a patient.
  • the negatively charged polynucleotides of the invention can be administered ⁇ e.g.,
  • compositions of the present invention can also be formulated and used as tablets, capsules or elixirs for oral administration; suppositories for rectal administration; sterile solutions; suspensions for injectable administration; and the other compositions known in the art.
  • the present invention also includes pharmaceutically acceptable formulations of the compounds described. These formulations include salts of the above compounds, e.g., acid addition salts, for example, salts of hydrochloric, hydrobromic, acetic acid, and benzene sulfonic acid.
  • a pharmacological composition or formulation refers to a composition or formulation in a form suitable for administration, e.g., local administration or systemic administration, into a cell or patient, including, for example, a human. Suitable forms, in part, depend upon the use or the route of entry, for example oral, transdermal, or by injection. Such forms should not prevent the composition or formulation from reaching a target cell ⁇ i.e., a cell to which the negatively charged polymer is desired to be delivered to). For example, pharmacological compositions injected into the blood stream should be soluble. Other factors are known in the art, and include considerations such as toxicity and forms which prevent the composition or formulation from exerting its effect.
  • local administration in vivo local abso ⁇ tion or accumulation of drugs in the specific tissue, organ, or compartment of the body.
  • Administration routes that can lead to local abso ⁇ tion include, without limitations: inhalation, direct injection, or dermatological applications.
  • systemic administration in vivo systemic abso ⁇ tion or accumulation of dmgs in the blood stream followed by distribution throughout the entire body.
  • Administration routes which lead to systemic abso ⁇ tion include, without limitations: intravenous, subcutaneous, intraperitoneal, inhalation, oral, intrapulmonary and intramuscular. Each of these administration routes expose the desired compound, e.g., nucleic acids, to an accessible diseased tissue.
  • the rate of entry of a dmg into the circulation has been shown to be a function of molecular weight or size.
  • a liposome or other dmg carrier comprising the compounds of the instant invention, for example PEG or phospholipids conjugates, can potentially localize the dmg, for example, in certain tissue types, such as the tissues of the reticular endothelial system (RES).
  • RES reticular endothelial system
  • a nucleic acid formulation that can facilitate the association of dmg with the surface of cells, such as, lymphocytes and macrophages is also useful. This approach can provide enhanced delivery of the dmg to target cells by taking advantage of the specificity of macrophage and lymphocyte immune recognition of abnormal cells.
  • nucleic acid molecules of the invention are administered to a patient with an inhaler or nebulizer, providing rapid local uptake of the nucleic acid molecules into relevant pulmonary tissues.
  • nucleic acid molecule or formulation comprising the nucleic acid molecule is administered to a patient systemically, for example by intravenous or subcutaneous injection, providing sustained uptake ofthe nucleic acid molecules into relevant bodily tissues.
  • pharmaceutically acceptable formulation is meant, a composition or formulation that allows for the effective distribution of the nucleic acid molecules of the instant invention in the physical location most suitable for their desired activity.
  • agents suitable for formulation with the nucleic acid molecules of the instant invention include: PEG conjugated nucleic acids, phospholipid conjugated nucleic acids, nucleic acids containing lipophilic moieties, phosphorothioates, P-glycoprotein inhibitors (such as Pluronic P85) which can enhance entry of dmgs into various tissues, for exaple the CNS (Jolliet-Riant and Tillement, 1999, Fundam. Clin. Pharmacol, 13, 16-26); biodegradable polymers, such as poly (DL-lactide-coglycolide) microspheres for sustained release delivery after implantation (Emerich, DF et al, 1999, Cell Transplant, 8, 47-58) Alkermes, Inc.
  • nanoparticles such as those made of polybutylcyanoacrylate, which can deliver dmgs across the blood brain barrier and can alter neuronal uptake mechanisms ⁇ Prog N eur opsychopharmacol Biol Psychiatry , 23, 941-949, 1999).
  • delivery strategies including CNS delivery of the nucleic acid molecules of the instant invention include material described in Boado et al, 1998, J. Pharm. Sci., 87, 1308-1315; Tyler et al, 1999, FEBS Lett., 421, 280-284; Pardridge et al, 1995, PNAS USA., 92, 5592- 5596; Boado, 1995, Adv.
  • the invention also features the use of the composition comprising surface-modified liposomes containing poly (ethylene glycol) lipids (PEG-modified, or long-circulating liposomes or stealth liposomes).
  • Nucleic acid molecules of the invention can also comprise covalently attached PEG molecules of various molecular weights. These formulations offer a method for increasing the accumulation of dmgs in target tissues. This class of dmg carriers resists opsonization and elimination by the mononuclear phagocytic system (MPS or RES), thereby enabling longer blood circulation times and enhanced tissue exposure for the encapsulated dmg (Lasic et al. Chem. Rev.
  • compositions prepared for storage or administration that include a pharmaceutically effective amount of the desired compounds in a pharmaceutically acceptable carrier or diluent.
  • Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A.R. Gennaro edit. 1985) hereby inco ⁇ orated by reference herein.
  • preservatives, stabilizers, dyes and flavoring agents can be provided. These include sodium benzoate, sorbic acid and esters of p- hydroxybenzoic acid.
  • antioxidants and suspending agents can be used.
  • a pharmaceutically effective dose is that dose required to prevent, inhibit the occurrence, or treat (alleviate a symptom to some extent, or all of the symptoms) of a disease state.
  • the pharmaceutically effective dose depends on the type of disease, the composition used, the route of administration, the type of mammal being treated, the physical characteristics of the specific mammal under consideration, concurrent medication, and other factors which those skilled in the medical arts will recognize. Generally, an amount between 0.1 mg/kg and 100 mg/kg body weight/day of active ingredients is administered dependent upon potency ofthe negatively charged polymer.
  • nucleic acid molecules of the invention and formulations thereof can be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • parenteral as used herein includes percutaneous, subcutaneous, intravascular (e.g., intravenous), intramuscular, or intrathecal injection or infusion techniques and the like.
  • a pharmaceutical formulation comprising a nucleic acid molecule of the invention and a pharmaceutically acceptable carrier.
  • One or more nucleic acid molecules of the invention can be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants, and if desired other active ingredients.
  • compositions containing nucleic acid molecules of the invention can be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
  • compositions intended for oral use can be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more such sweetening agents, flavoring agents, coloring agents or preservative agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets.
  • excipients can be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, com starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets can be uncoated or they can be coated by known techniques. In some cases such coatings can be prepared by known techniques to delay disintegration and abso ⁇ tion in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monosterate or glyceryl distearate can be employed.
  • Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropyl-methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents can be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monoole
  • the aqueous suspensions can also contain one or more preservatives, for example ethyl, or n-propyl p- hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • preservatives for example ethyl, or n-propyl p- hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl p- hydroxybenzoate
  • flavoring agents for example ethyl, or n-propyl p- hydroxybenzoate
  • sweetening agents such as sucrose or saccharin.
  • Oily suspensions can be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions can contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents and flavoring agents can be added to provide palatable oral preparations.
  • These compositions can be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerin, glycerin, glycerin, glycerin, glycerin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol
  • compositions of the invention can also be in the form of oil-in-water emulsions.
  • the oily phase can be a vegetable oil or a mineral oil or mixtures of these.
  • Suitable emulsifying agents can be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions can also contain sweetening and flavoring agents.
  • Syrups and elixirs can be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol, glucose or sucrose. Such formulations can also contain a demulcent, a preservative and flavoring and coloring agents.
  • the pharmaceutical compositions can be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents that have been mentioned above.
  • the sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • Suitable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono-or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the nucleic acid molecules of the invention can also be administered in the form of suppositories, e.g., for rectal administration ofthe dmg.
  • suppositories e.g., for rectal administration ofthe dmg.
  • These compositions can be prepared by mixing the dmg with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the dmg.
  • suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the dmg.
  • Such materials include cocoa butter and polyethylene glycols.
  • Nucleic acid molecules of the invention can be administered parenterally in a sterile medium.
  • the dmg depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle.
  • adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.
  • Dosage levels of the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per patient per day).
  • the amount of active ingredient that can be combined with the carrier materials to produce a single dosage form varies depending upon the host treated and the particular mode of administration.
  • Dosage unit forms generally contain between from about 1 mg to about 500 mg of an active ingredient.
  • the specific dose level for any particular patient depends upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, dmg combination and the severity ofthe particular disease undergoing therapy.
  • the composition can also be added to the animal feed or drinking water. It can be convenient to formulate the animal feed and drinking water compositions so that the animal takes in a therapeutically appropriate quantity of the composition along with its diet. It can also be convenient to present the composition as a premix for addition to the feed or drinking water.
  • nucleic acid molecules of the present invention can also be administered to a patient in combination with other therapeutic compounds to increase the overall therapeutic effect.
  • the use of multiple compounds to treat an indication can increase the beneficial effects while reducing the presence of side effects.
  • nucleic acid molecules of the instant invention can be expressed within cells from eukaryotic promoters ⁇ e.g., Izant and Weintraub, 1985, Science, 229, 345; McGarry and Lindquist, 1986, Proc Natl. Acad. Sci., USA 83, 399; Scanlon et al, 1991, Proc. Natl. Acad. Sci. USA, 88, 10591-5; Kashani-Sabet et al, 1992, Antisense Res. Dev., 2, 3-15; Dropulic et al, 1992, J. Virol, 66, 1432-41; Weerasinghe et al, 1991, J.
  • nucleic acids can be augmented by their release from the primary transcript by a enzymatic nucleic acid (Draper et al, PCT WO 93/23569, and Sullivan et al, PCT WO 94/02595; Ohkawa et al, 1992, Nucleic Acids Symp. Ser., 27, 15-6; Taira et al, 1991, Nucleic Acids Res., 19, 5125-30; Ventura et al, 1993, Nucleic Acids Res., 21, 3249-55; Chowrira et al, 1994, J. Biol. Chem., 269, 25856; all of these references are hereby inco ⁇ orated in their totalities by reference herein).
  • a enzymatic nucleic acid Draper et al, PCT WO 93/23569, and Sullivan et al, PCT 94/02595; Ohkawa et al, 1992, Nucleic Acids Symp. Ser., 27,
  • R ⁇ A molecules of the present invention can be expressed from transcription units (see for example Couture et al, 1996, TIG, 12, 510) inserted into D ⁇ A or R ⁇ A vectors.
  • the recombinant vectors can be D ⁇ A plasmids or viral vectors. Ribozyme expressing viral vectors can be constmcted based on, but not limited to, adeno-associated vims, retrovims, adenovims, or alphavims.
  • the recombinant vectors capable of expressing the nucleic acid molecules can be delivered as described above, and persist in target cells. Alternatively, viral vectors can be used that provide for transient expression of nucleic acid molecules.
  • nucleic acid molecule expressing vectors can be systemic, such as by intravenous or intramuscular administration, by administration to target cells ex-planted from the patient followed by reintroduction into the patient, or by any other means that would allow for introduction into the desired target cell (for a review see Couture et al, 1996, TIG., 12, 510).
  • the invention features an expression vector comprising a nucleic acid sequence encoding at least one of the nucleic acid molecules of the instant invention is disclosed.
  • the nucleic acid sequence encoding the nucleic acid molecule of the instant invention is operably linked in a manner that allows expression of that nucleic acid molecule.
  • the invention features an expression vector comprising: a) a transcription initiation region ⁇ e.g., eukaryotic pol I, II or m initiation region); b) a transcription termination region ⁇ e.g., eukaryotic pol I, II or m termination region); c) a nucleic acid sequence encoding at least one of the nucleic acid catalyst of the instant invention; and wherein said sequence is operably linked to said initiation region and said termination region, in a manner that allows expression and/or delivery of said nucleic acid molecule.
  • the vector can optionally include an open reading frame (ORF) for a protein operably linked on the 5' side or the 3 '-side ofthe sequence encoding the nucleic acid catalyst ofthe invention; and/or an intron (intervening sequences).
  • ORF open reading frame
  • telomere sequences Transcription of the nucleic acid molecule sequences are driven from a promoter for eukaryotic R ⁇ A polymerase I (pol I), R ⁇ A polymerase II (pol U), or R ⁇ A polymerase UI (pol UI). Transcripts from pol ⁇ or pol UI promoters are expressed at high levels in all cells; the levels of a given pol ⁇ promoter in a given cell type depends on the nature of the gene regulatory sequences (enhancers, silencers, etc.) present nearby.
  • Prokaryotic R ⁇ A polymerase promoters are also used, providing that the prokaryotic R ⁇ A polymerase enzyme is expressed in the appropriate cells (Elroy-Stein and Moss, 1990, Proc. Natl. Acad. Sci.
  • nucleic acid molecules such as ribozymes expressed from such promoters can function in mammalian cells (e.g. Kashani-Sabet et al, 1992, Antisense Res. Dev., 2, 3- 15; Ojwang et al, 1992, Proc. Natl. Acad. Sci.
  • transcription units such as the ones derived from genes encoding U6 small nuclear (snRNA), transfer RNA (tRNA) and adenovims VA RNA are useful in generating high concentrations of desired RNA molecules such as ribozymes in cells (Thompson et al, supra; Couture and Stinchcomb, 1996, supra; Noonberg et al, 1994, Nucleic Acid Res., 22, 2830; Noonberg et al, US Patent No. 5,624,803; Good et al, 1997, Gene Ther., 4, 45; Beigelman et al, International PCT Publication No. WO 96/18736; all of these publications are inco ⁇ orated by reference herein).
  • ribozyme transcription units can be inco ⁇ orated into a variety of vectors for introduction into mammalian cells, including but not restricted to, plasmid DNA vectors, viral DNA vectors (such as adenovims or adeno-associated vims vectors), or viral RNA vectors (such as retroviral or alphavims vectors) (for a review see Couture and Stinchcomb, 7996, supra).
  • plasmid DNA vectors such as adenovims or adeno-associated vims vectors
  • viral RNA vectors such as retroviral or alphavims vectors
  • the invention features an expression vector comprising a nucleic acid sequence encoding at least one of the nucleic acid molecules of the invention, in a manner that allows expression of that nucleic acid molecule.
  • the expression vector comprises in one embodiment; a) a transcription initiation region; b) a transcription termination region; c) a nucleic acid sequence encoding at least one said nucleic acid molecule; and wherein said sequence is operably linked to said initiation region and said termination region, in a manner that allows expression and/or delivery of said nucleic acid molecule.
  • the expression vector comprises: a) a transcription initiation region; b) a transcription termination region; c) an open reading frame; d) a nucleic acid sequence encoding at least one said nucleic acid molecule, wherein said sequence is operably linked to the 3'-end of said open reading frame; and wherein said sequence is operably linked to said initiation region, said open reading frame and said termination region, in a manner that allows expression and/or delivery of said nucleic acid molecule.
  • the expression vector comprises: a) a transcription initiation region; b) a transcription termination region; c) an intron; d) a nucleic acid sequence encoding at least one said nucleic acid molecule; and wherein said sequence is operably linked to said initiation region, said intron and said termination region, in a manner which allows expression and/or delivery of said nucleic acid molecule.
  • the expression vector comprises: a) a transcription initiation region; b) a transcription termination region; c) an intron; d) an open reading frame; e) a nucleic acid sequence encoding at least one said nucleic acid molecule, wherein said sequence is operably linked to the 3'-end of said open reading frame; and wherein said sequence is operably linked to said initiation region, said intron, said open reading frame and said termination region, in a manner which allows expression and/or delivery of said nucleic acid molecule.
  • Example 1 Nucleic acid molecules targeting PTGDS. ADORAl and PTGDR RNA
  • the invention features novel nucleic acid-based molecules, for example, enzymatic nucleic acid molecules, allozymes, antisense nucleic acids, 2-5A antisense chimeras, triplex forming oligonucleotides, decoy RNA, dsRNA, siRNA, aptamers, and antisense nucleic acids containing RNA cleaving chemical groups, and methods to modulate gene expression, for example, genes encoding prostaglandin D2 receptor (PTGDR), prostaglandin D2 synthetase (PTGDS), and adenosine receptors (AR) such as adenosine receptor Al, A2a, A2b, and A3.
  • PTGDR prostaglandin D2 receptor
  • PTGDS prostaglandin D2 synthetase
  • AR adenosine receptors
  • the instant invention features nucleic-acid based molecules and methods to modulate the expression of PTGDR, PTGDS, and adeno
  • the invention features one or more nucleic acid-based molecules and methods that independently or in combination modulate the expression of gene(s) encoding prostaglandin D2 receptors (PTGDR), prostaglandin D2 synthetase (PTGDS) and adenosine receptors such as ADORAl.
  • PAGDR prostaglandin D2 receptor
  • PAGDS prostaglandin D2 synthetase
  • ADORAl adenosine receptors
  • the present invention features nucleic acid molecules that modulate the expression of prostaglandin D2 receptor (PTGDR) gene, for example Genbank Accession Nos. U31332 and U31099, prostaglandin D2 synthetase (PTGDS) gene, for example Genbank Accession No. NM_000954, and Adenosine Al receptor (ADORAl), for example Genbank Accession No. NM_000674.
  • the invention features an enzymatic nucleic acid molecule comprising a sequence selected from the group consisting of SEQ ID NOs: 11666-13262.
  • the invention features an enzymatic nucleic acid molecule comprising at least one binding arm wherein one or more of said binding arms comprises a sequence complementary to a sequence selected from the group consisting of SEQ ED NOs: 4415-5483.
  • the invention features an antisense nucleic acid molecule comprising a sequence complementary to a sequence selected from the group consisting of SEQ ID NOs: 4415-5483.
  • an enzymatic nucleic acid molecule, antisense nucleic acid molecule, 2-5A antisense chimera, triplex forming oligonucleotide, decoy RNA, dsRNA, siRNA, aptamer, or antisense nucleic acids containing RNA cleaving chemical groups of the invention is adapted to treat asthma.
  • an enzymatic nucleic acid molecule of the invention has an endonuclease activity to cleave RNA encoded by a PTGDS and/or PTGDR gene.
  • an enzymatic nucleic acid molecule of the invention is in a hammerhead, taozyme, Zinzyme, DNAzyme, Amberzyme, or G-cleaver configuration.
  • an enzymatic nucleic acid molecule of the invention having a hammerhead configuration comprises a sequence complementary to a sequence having SEQ
  • an enzymatic nucleic acid molecule of invention having a hammerhead configuration comprises a sequence having SEQ ID NOs:
  • an enzymatic nucleic acid molecule of the invention having an taozyme configuration comprises a sequence complementary to a sequence having SEQ
  • an enzymatic nucleic acid molecule of invention having an taozyme configuration comprises a sequence having SEQ ID NOs:
  • an enzymatic nucleic acid molecule of the invention having a Zinzyme configuration comprises a sequence complementary to a sequence having SEQ ID NO: 1
  • an enzymatic nucleic acid molecule of invention having a Zinzyme configuration comprises a sequence having SEQ DD NOs: 12269-
  • an enzymatic nucleic acid molecule of the invention having a DNAzyme configuration comprises a sequence complementary to a sequence having SEQ ED
  • an enzymatic nucleic acid molecule of invention having a DNAzyme configuration comprises a sequence having SEQ ED NOs:
  • an enzymatic nucleic acid molecule of the invention having an Amberzyme configuration comprises a sequence complementary to a sequence having
  • an enzymatic nucleic acid molecule of invention having an Amberzyme configuration comprises a sequence having SEQ ED NOs: 12843-13262.
  • an enzymatic nucleic acid molecule of the invention comprises between 8 and 100 bases complementary to the RNA of PTGDS, ADORAl and/or PTGDR gene, ta another embodiment, an enzymatic nucleic acid molecule ofthe invention comprises between 14 and 24 bases complementary to a RNA molecule of a PTGDS or PTGDR gene.
  • an enzymatic nucleic acid molecule, antisense nucleic acid molecule, 2-5A antisense chimera, triplex forming oligonucleotide, decoy RNA, dsRNA, siRNA, aptamer, or antisense nucleic acids containing RNA cleaving chemical groups of the invention is chemically synthesized.
  • a antisense chimera, triplex forming oligonucleotide, decoy RNA, dsRNA, siRNA, aptamer, or antisense nucleic acids containing RNA cleaving chemical groups of the invention comprises at least one 2'-sugar modification.
  • an enzymatic nucleic acid molecule, antisense nucleic acid molecule, 2-5A antisense chimera, triplex forming oligonucleotide, decoy RNA, dsRNA, siRNA, aptamer, or antisense nucleic acids containing RNA cleaving chemical groups of the invention comprises at least one nucleic acid base modification.
  • an enzymatic nucleic acid molecule, antisense nucleic acid molecule, 2-5A antisense chimera, triplex forming oligonucleotide, decoy RNA, dsRNA, siRNA, aptamer, or antisense nucleic acids containing RNA cleaving chemical groups of the invention comprises at least one phosphate backbone modification.
  • the invention features a mammalian cell, for example a human cell, including the enzymatic nucleic acid molecule ofthe invention.
  • the invention features a method of reducing PTGDS, ADORAl and/or PTGDR expression or activity in a cell, comprising contacting the cell with an enzymatic nucleic acid molecule of the invention, under conditions suitable for the reduction.
  • the invention features a method of reducing PTGDS, ADORAl and/or PTGDR expression or activity in a cell, comprising the step of contacting the cell with an antisense nucleic acid molecule of the invention under conditions suitable for the reduction.
  • the invention features a method of treatment of a patient having a condition associated with the level of PTGDS, ADORAl and/or PTGDR, comprising contacting cells of the patient with an enzymatic nucleic acid molecule of the invention, under conditions suitable for the treatment.
  • the invention features a method of treatment of a patient having a condition associated with the level of PTGDS, ADORAl and/or PTGDR, comprising contacting cells of the patient with an antisense nucleic acid molecule of the invention, under conditions suitable for the treatment.
  • a method of treatment of a patient having a condition associated with the level of PTGDS, ADORAl and/or PTGDR is featured, wherein the method further comprises the use of one or more dmg therapies under conditions suitable for the treatment.
  • the invention features a method for treatment of asthma, allergic rhinitis, or atopic dermatitis under conditions suitable for the treatment.
  • the invention features a method of cleaving a RNA molecule of PTGDS, ADORAl and/or PTGDR gene comprising contacting an enzymatic nucleic acid molecule ofthe invention with a RNA molecule of a PTGDS, ADORAl and/or PTGDR gene under conditions suitable for the cleavage, for example, wherein the cleavage is carried out in the presence of a divalent cation, such as Mg2+.
  • a divalent cation such as Mg2+.
  • an enzymatic nucleic acid molecule of the invention comprises a cap stmcture, for example a 3',3'-linked or 5',5'-linked deoxyabasic ribose derivative, wherein the cap stmcture is at the 5 '-end, or 3 '-end, or both the 5 '-end and the 3 '-end of the enzymatic nucleic acid molecule.
  • a cap stmcture for example a 3',3'-linked or 5',5'-linked deoxyabasic ribose derivative, wherein the cap stmcture is at the 5 '-end, or 3 '-end, or both the 5 '-end and the 3 '-end of the enzymatic nucleic acid molecule.
  • an antisense nucleic acid molecule of the invention comprises a cap stmcture, for example a 3',3'-linked or 5',5'-linked deoxyabasic ribose derivative, wherein the cap stmcture is at the 5 '-end, or 3 '-end, or both the 5 '-end and the 3 '-end of the antisense nucleic acid molecule.
  • the invention features an expression vector comprising a nucleic acid sequence encoding at least one enzymatic nucleic acid molecule of the invention, in a manner which allows expression ofthe nucleic acid molecule.
  • the invention features a mammalian cell, for example, a human cell, including an expression vector ofthe invention.
  • the expression vector of the invention further comprises a sequence for an antisense nucleic acid molecule complementary to a RNA molecule of a PTGDS, ADORAl and/or PTGDR gene.
  • an expression vector of the invention comprises a nucleic acid sequence encoding two or more enzymatic nucleic acid molecules, which can be the same or different.
  • the invention features a method for treatment of asthma, allergic rhinitis, or atopic dermatitis, comprising administering to a patient an enzymatic nucleic acid molecule, antisense nucleic acid molecule, 2-5A antisense chimera, triplex forming oligonucleotide, decoy RNA, dsRNA, siRNA, aptamer, or antisense nucleic acid containing RNA cleaving chemical groups of the invention, under conditions suitable for the treatment, including administering to the patient one or more other therapies, for example, inhalant anti-inflammatories, bronchodilators, adenosine inhibitors and adenosine Al receptor inhibitors.
  • therapies for example, inhalant anti-inflammatories, bronchodilators, adenosine inhibitors and adenosine Al receptor inhibitors.
  • an enzymatic nucleic acid molecule or antisense nucleic acid molecule of the invention comprises at least five ribose residues, at least ten 2'-O-methyl modifications, and a 3'- end modification, such as a 3 '-3' inverted abasic moiety
  • an enzymatic nucleic acid molecule or antisense nucleic acid molecule of the invention further comprises phosphorothioate linkages on at least three ofthe 5' terminal nucleotides.
  • the invention features a method of administering to a mammal, for example a human, an enzymatic nucleic acid molecule, antisense nucleic acid molecule, 2- 5 A antisense chimera, triplex forming oligonucleotide, decoy RNA, dsRNA, siRNA, aptamer, or antisense nucleic acid containing RNA cleaving chemical groups of the invention, comprising contacting the mammal with the nucleic acid molecule under conditions suitable for the administration, for example, in the presence of a delivery reagent such as a lipid, cationic lipid, phospholipid, or liposome.
  • a delivery reagent such as a lipid, cationic lipid, phospholipid, or liposome.
  • the invention features a method of administering to a mammal an enzymatic nucleic acid molecule, antisense nucleic acid molecule, 2-5A antisense chimera, triplex forming oligonucleotide, decoy RNA, dsRNA, siRNA, aptamer, or antisense nucleic acid containing RNA cleaving chemical groups of the invention in conjunction with a therapeutic agent, comprising contacting the mammal, for example a human, with the nucleic acid molecule and the therapeutic agent under conditions suitable for the administration.
  • the invention features the use of an enzymatic nucleic acid molecule, which can be in a hammerhead, NCH, G-cleaver, Amberzyme, Zinzyme, and/or DNAzyme motif, to down-regulate the expression of a PTGDS, an ADORAl and/or a PTGDR gene.
  • an enzymatic nucleic acid molecule which can be in a hammerhead, NCH, G-cleaver, Amberzyme, Zinzyme, and/or DNAzyme motif, to down-regulate the expression of a PTGDS, an ADORAl and/or a PTGDR gene.
  • ADORAl and PTGDR-specific RNAs represent a novel therapeutic approach to treat a variety of allergic diseases or conditions, including but not limited to asthma, allergic rhinitis, atopic dermatitis, and/or other allergic or inflammatory diseases and conditions which respond to the modulation of PTGDS, ADORAl and or PTGDR expression.
  • a nucleic acid molecule that modulates, for example, down- regulates, PTGDS replication or expression comprises between 8 and 100 bases complementary to a RNA molecule of PTGDS.
  • a nucleic acid molecule that modulates PTGDS replication or expression comprises between 14 and 24 bases complementary to a RNA molecule of PTGDS.
  • a nucleic acid molecule that modulates, for example, down- regulates, PTGDR replication or expression comprises between 8 and 100 bases complementary to a RNA molecule of PTGDR.
  • a nucleic acid molecule that modulates PTGDR replication or expression comprises between 14 and 24 bases complementary to a RNA molecule of PTGDR.
  • a nucleic acid molecule that modulates, for example, down- regulates, ADORAl replication or expression comprises between 8 and 100 bases complementary to a RNA molecule of ADORAl.
  • a nucleic acid molecule that modulates ADORAl replication or expression comprises between 14 and 24 bases complementary to a RNA molecule of ADORAl.
  • the invention provides a method for producing a class of nucleic acid-based gene modulating agents that exhibit a high degree of specificity for the RNA of a desired target.
  • the enzymatic nucleic acid molecule is can be targeted to a highly conserved sequence region of target RNAs encoding PTGDS, ADORAl and/or PTGDR (e.g., PTGDS, ADORAl and/or PTGDR genes) such that specific treatment of a disease or condition can be provided with either one or several nucleic acid molecules of the invention.
  • PTGDS e.g., PTGDS, ADORAl and/or PTGDR genes
  • Such nucleic acid molecules can be delivered exogenously to specific tissue or cellular targets as required.
  • the nucleic acid molecules ⁇ e.g., ribozymes and antisense
  • Nucleic acid-based inhibitors of PTGDS, ADORAl and PTGDR expression are useful for the prevention and/or treatment of allergic diseases or conditions, including but not limited to asthma, allergic rhinitis, atopic dermatitis, and any other diseases or conditions that are related to or will respond to the levels of PTGDS, ADORAl and/or PTGDR in a cell or tissue, alone or in combination with other therapies.
  • the reduction of PTGDS, ADORAl and/or PTGDR expression specifically PTGDS, ADORAl and or PTGDR gene RNA levels
  • nucleic acid molecules of the instant invention can be used to treat diseases or conditions discussed above.
  • the patient can be treated, or other appropriate cells can be treated, as is evident to those skilled in the art, individually or in combination with one or more dmgs under conditions suitable for the treatment.
  • the described molecules can be used in combination with other known treatments to treat conditions or diseases discussed above.
  • the described molecules can be used in combination with one or more known therapeutic agents to treat allergic diseases or conditions, including but not limited to asthma, allergic rhinitis, atopic dermatitis, and/or other allergic or inflammatory diseases and conditions which respond to the modulation of PTGDS, ADORAl and/or PTGDR expression.
  • the invention features nucleic acid-based inhibitors ⁇ e.g., enzymatic nucleic acid molecules (e.g., ribozymes), antisense nucleic acids, 2-5A antisense chimeras, triplex DNA, antisense nucleic acids containing RNA cleaving chemical groups) and methods for their use to down regulate or inhibit the expression of genes ⁇ e.g., PTGDS, ADORAl and/or PTGDR) capable of progression and/or maintenance allergic diseases or conditions, including but not limited to asthma, allergic rhinitis, atopic dermatitis, and/or other allergic or inflammatory diseases and conditions which respond to the modulation of PTGDS, ADORAl and/or PTGDR expression.
  • enzymatic nucleic acid molecules e.g., ribozymes
  • antisense nucleic acids e.g., 2-5A antisense chimeras, triplex DNA
  • antisense nucleic acids containing RNA cleaving chemical groups
  • the sequence of human PTGDS, ADORAl and PTGDR genes are screened for accessible sites using a computer-folding algorithm. Regions of the RNA that do not form secondary folding stmctures and contained potential enzymatic nucleic acid molecule and/or antisense binding/cleavage sites are identified. The sequences of PTGDR binding/cleavage sites are shown in Tables XIX-XXIII. Selection of Enzymatic Nucleic Acid Cleavage Sites in Human PTGDS, ADORAl and PTGDR RNA
  • Enzymatic nucleic acid molecule target sites are chosen by analyzing sequences of Human PTGDS (Genbank accession No: NM 000954), ADORAl (Genbank accession No: NM_000674) and PTGDR gene (Genbank accession Nos: U31332 and U31099) and prioritizing the sites on the basis of folding. Enzymatic nucleic acid molecules are designed that can bind each target and are individually analyzed by computer folding (Christoffersen et al, 1994 J. Mol. Struc Theochem, 311, 273; Jaeger et al, 1989, Proc. Natl. Acad. Sci.
  • binding arm lengths can be chosen to optimize activity. Generally, at least 4 bases on each arm are able to bind to, or otherwise interact with, the target RNA.
  • Enzymatic nucleic acid molecules and antisense constmcts are designed to anneal to various sites in the RNA message.
  • the binding arms ofthe enzymatic nucleic acid molecules are complementary to the target site sequences described above, while the antisense constmcts are fully complementary to the target site sequences described above.
  • the enzymatic nucleic acid molecules and antisense constmcts were chemically synthesized. The method of synthesis used followed the procedure for normal RNA synthesis as described above and in Usman et al, (1987 J. Am. Chem.
  • Enzymatic nucleic acid molecules and antisense constmcts are also synthesized from DNA templates using bacteriophage T7 RNA polymerase (Milligan and Uhlenbeck, 1989, Methods Enzymol. 180, 51). Enzymatic nucleic acid molecules and antisense constmcts are purified by gel electrophoresis using general methods or are purified by high pressure liquid chromatography (HPLC; See Wincott et al, supra; the totality of which is hereby inco ⁇ orated herein by reference) and are resuspended in water. The sequences of the chemically synthesized enzymatic nucleic acid molecules used in this study are shown below in Tables XIX-XXIII.
  • sequences of the chemically synthesized antisense constmcts used in this study are complementary sequences to the Substrate sequences shown below as in Tables XIX-XXIII.
  • PTGDR RNA are designed and synthesized as described above. These enzymatic nucleic acid molecules can be tested for cleavage activity in vitro, for example, using the following procedure.
  • the target sequences and the nucleotide location within the PTGDR RNA are given in Tables XIX-XXIII.
  • Full-length or partially full-length, internally-labeled target RNA for enzymatic nucleic acid molecule cleavage assay is prepared by in vitro transcription in the presence of [a- 32 p] CTP, passed over a G 50 Sephadex column by spin chromatography and
  • substrates are 5'- P-end labeled using T4 polynucleotide kinase enzyme.
  • Assays are performed by pre-warming a 2X concentration of purified enzymatic nucleic acid molecule in enzymatic nucleic acid molecule cleavage buffer (50 mM Tris-HCl, pH 7.5 at 37°C, 10 mM MgCl2) and the cleavage reaction was initiated by adding the 2X enzymatic nucleic acid molecule mix to an equal volume of substrate RNA (maximum of 1-5 nM) that was also pre-warmed in cleavage buffer.
  • enzymatic nucleic acid molecule cleavage buffer 50 mM Tris-HCl, pH 7.5 at 37°C, 10 mM MgCl2
  • assays are carried out for 1 hour at 37 C using a final concentration of either 40 nM or 1 mM enzymatic nucleic acid molecule, i.e., enzymatic nucleic acid molecule excess.
  • the reaction is quenched by the addition of an equal volume of 95% formamide, 20 mM EDTA, 0.05%) bromophenol blue and 0.05%> xylene cyanol after which the sample is heated o to 95 C for 2 minutes, quick chilled and loaded onto a denaturing polyacrylamide gel.
  • Substrate RNA and the specific RNA cleavage products generated by enzymatic nucleic acid molecule cleavage are visualized on an autoradiograph of the gel. The percentage of cleavage is determined by Phosphor Imager® quantitation of bands representing the intact substrate and the cleavage products.
  • this model can be used to evaluate mice that are treated with nucleic acid molecules of the invention and can furthermore be used as a positive control in determining the response of mice treated with nucleic acid molecules of the invention by using such factors as airway obstruction, lung capacity, and bronchiolar alveolar lavage (BAL) fluid in the evaluation.
  • BAL bronchiolar alveolar lavage
  • PTGDR Two human cell lines, NPE cells and NCB-20 cells are known to express PTGDR. Cloned human PTGDR has been expressed in CHO and COS7 cells and used in various studies. These PTGDR expressing lung cell lines can be used in cell culture assays to evaluate nucleic acid molecules of the invention. A primary endpoint in these experiments would be the RT-PCR analysis of PTGDR mRNA expression in PTGDR expressing cells, ta addition, ligand binding assays can be developed where binding of PTGDS can be evaluated in response to treatment with nucleic acid molecules ofthe invention.
  • the nucleic acid molecules of the present invention can be used in assays to diagnose disease state related of PTGDS, ADORAl and/or PTGDR levels.
  • the nucleic acid molecules can be used to treat disease state related to PTGDS, ADORAl and or PTGDR levels.
  • Particular degenerative and disease states that can be associated with PTGDS, ADORAl and PTGDR levels include, but are not limited to allergic diseases and conditions, including but not limited to asthma, allergic rhinitis, atopic dermatitis, and any other diseases or conditions that are related to or will respond to the levels of PTGDS, ADORAl and or
  • the nucleic acid molecules of this invention can be used as diagnostic tools to examine genetic drift and mutations within diseased cells or to detect the presence of PTGDS, ADORAl and/or PTGDR RNA in a cell.
  • the close relationship between enzymatic nucleic acid molecule activity and the stmcture of the target RNA allows the detection of mutations in any region of the molecule that alters the base- pairing and three-dimensional stmcture of the target RNA.
  • multiple enzymatic nucleic acid molecules described in this invention one can map nucleotide changes which are important to RNA stmcture and function in vitro, as well as in cells and tissues.
  • Cleavage of target RNAs with enzymatic nucleic acid molecules can be used to inhibit gene expression and define the role (essentially) of specified gene products in the progression of disease. In this manner, other genetic targets can be defined as important mediators ofthe disease.
  • combinational therapies e.g., multiple enzymatic nucleic acid molecules targeted to different genes, enzymatic nucleic acid molecules coupled with known small molecule inhibitors, or intermittent treatment with combinations of enzymatic nucleic acid molecules and/or other chemical or biological molecules).
  • enzymatic nucleic acid molecules of this invention include detection ofthe presence of mRNAs associated with PTGDS, ADORAl or PTGDR-related condition. Such RNA is detected by determining the presence of a cleavage product after treatment with an enzymatic nucleic acid molecule using standard methodology.
  • enzymatic nucleic acid molecules which cleave only wild-type or mutant forms of the target RNA are used for the assay.
  • the first enzymatic nucleic acid molecule is used to identify wild-type RNA present in the sample and the second enzymatic nucleic acid molecule is used to identify mutant RNA in the sample.
  • synthetic substrates of both wild-type and mutant RNA are cleaved by both enzymatic nucleic acid molecules to demonstrate the relative enzymatic nucleic acid molecule efficiencies in the reactions and the absence of cleavage of the "non-targeted" RNA species.
  • the cleavage products from the synthetic substrates also serve to generate size markers for the analysis of wild-type and mutant RNAs in the sample population.
  • each analysis requires two enzymatic nucleic acid molecules, two substrates and one unknown sample which is combined into six reactions.
  • the presence of cleavage products is determined using an RNAse protection assay so that full-length and cleavage fragments of each RNA can be analyzed in one lane of a polyacrylamide gel. It is not absolutely required to quantify the results to gain insight into the expression of mutant RNAs and putative risk of the desired phenotypic changes in target cells.
  • RNA whose protein product is implicated in the development of the phenotype ⁇ i.e., PTGDS/PTGDR) is adequate to establish risk. If probes of comparable specific activity are used for both transcripts, then a qualitative comparison of RNA levels will be adequate and will decrease the cost ofthe initial diagnosis. Higher mutant form to wild-type ratios are correlated with higher risk whether RNA levels are compared qualitatively or quantitatively.
  • the use of enzymatic nucleic acid molecules in diagnostic applications contemplated by the instant invention is described, for example, in George et al, US Patent Nos. 5,834,186 and 5,741,679, Shih et al, US Patent No.
  • Example 2 Nucleic acid inhibition of NOGO and NOGO receptor target RNA
  • the invention features novel nucleic acid-based molecules [e.g., enzymatic nucleic acid molecules (ribozymes), antisense nucleic acids, 2-5A antisense chimeras, triplex DNA, decoy RNA, aptamers, siRNA, antisense nucleic acids containing RNA cleaving chemical groups] and methods to modulate gene expression, for example, genes encoding certain myelin proteins that inhibit or are involved in the inhibition of neurite growth, including axonal regeneration in the CNS.
  • the instant invention features nucleic-acid based techniques to inhibit the expression of NOGO-A (Accession No. AJ251383), NOGO-B (Accession No.
  • NOGO-C accession No. AJ251384
  • NOGO-66 receptor Accession No AF283463, Fournier et al, 2001, Nature, 409, 341-346
  • NI-35 NI-220
  • NI-250 myelin-associated glycoprotein
  • tenascin-R Genbank Accession No X98085
  • NG-2 Genbank Accession No X61945
  • the invention features the use of one or more of the nucleic acid-based techniques independently or in combination to inhibit the expression or function of the gene(s) encoding NOGO-A, NOGO-B, NOGO-C, NI-35, NI-220, NI-250, myelin- associated glycoprotein, tenascin-R, NG-2 and/or their corresponding receptors.
  • the invention features the use of nucleic acid-based techniques to specifically inhibit the expression of NOGO gene (Genbank Accession No. AB020693) and NOGO-66 receptor (Genbank Accession No. AF283463).
  • RNAs represent a novel therapeutic approach to treat a variety of pathologic indications, including but not limited to CNS injury and cerebrovascular accident (CVA, stroke), Alzheimer's disease, dementia, multiple sclerosis (MS), chemotherapy-induced neuropathy, amyotrophic lateral sclerosis (ALS), Parkinson's disease, ataxia, Huntington's disease, Creutzfeldt- Jakob disease, muscular dystrophy, and/or other neurodegenerative disease states which respond to the modulation of NOGO and NOGO receptor expression.
  • CVA CNS injury and cerebrovascular accident
  • MS multiple sclerosis
  • chemotherapy-induced neuropathy adenotrophic lateral sclerosis
  • Parkinson's disease ataxia
  • Huntington's disease Creutzfeldt- Jakob disease
  • muscular dystrophy and/or other neurodegenerative disease states which respond to the modulation of NOGO and NOGO receptor expression.
  • a nucleic acid molecule that inhibits NOGO and/or NOGO receptor replication or expression can comprise between 12 and 100 bases complementary to a RNA molecule of NOGO or NOGO receptor, ta another embodiment, a nucleic acid molecule that inhibits NOGO or NOGO receptor replication or expression comprises between 14 and 24 bases complementary to a RNA molecule of NOGO or NOGO receptor.
  • the invention provides a method for producing a class of nucleic acid-based gene inhibiting agents which exhibit a high degree of specificity for the RNA of a desired target.
  • the enzymatic nucleic acid molecule is preferably targeted to a highly conserved sequence region of target RNAs encoding NOGO-A, NOGO-B, NOGO-C and/or receptor proteins (specifically NOGO and NOGO receptor genes) such that specific treatment of a disease or condition can be provided with either one or several nucleic acid molecules of the invention.
  • Such nucleic acid molecules can be delivered exogenously to specific tissue or cellular targets as required.
  • the nucleic acid molecules ⁇ e.g., ribozymes and antisense
  • the nucleic acid-based inhibitors of NOGO and NOGO receptor expression are useful for the prevention and/or treatment of diseases and conditions such CNS injury, cerebrovascular accident (CVA, stroke), Alzheimer's disease, dementia, multiple sclerosis (MS), chemotherapy-induced neuropathy, muscular dystrophy and any other diseases or conditions that are related to or will respond to the levels of NOGO and/or NOGO receptor in a cell or tissue, alone or in combination with other therapies, ta addition, NOGO and/or NOGO receptor inhibition can be used as a therapeutic target for abrogating CNS neuronal growth inhibition; a situation that can selectively regenerate damaged or lesioned CNS tissue to restore specific reflex and/or locomotor functions.
  • diseases and conditions such CNS injury, cerebrovascular accident (CVA, stroke), Alzheimer's disease, dementia, multiple sclerosis (MS), chemotherapy-induced neuropathy, muscular dystrophy and any other diseases or conditions that are related to or will respond to the levels of NOGO and/or NOGO receptor in a cell or tissue, alone or in combination with
  • the described molecules can be used in combination with other known treatments to treat conditions or diseases discussed above.
  • the described molecules can be used in combination with one or more known therapeutic agents to treat CNS injury, spinal cord injury, cerebrovascular accident (CVA, stroke), Alzheimer's disease, dementia, multiple sclerosis (MS), chemotherapy-induced neuropathy, amyotrophic lateral sclerosis (ALS), Parkinson's disease, ataxia, Huntington's disease, Creutzfeldt- Jakob disease, muscular dystrophy, and/or other neurodegenerative disease states which respond to the modulation of NOGO and/or NOGO receptor expression.
  • CVA cerebrovascular accident
  • MS multiple sclerosis
  • chemotherapy-induced neuropathy amyotrophic lateral sclerosis
  • Parkinson's disease ataxia
  • Huntington's disease Creutzfeldt- Jakob disease
  • muscular dystrophy and/or other neurodegenerative disease states which respond to the modulation of NOGO and/or NOGO receptor expression.
  • the invention features nucleic acid-based inhibitors ⁇ e.g., enzymatic nucleic acid molecules (eg; ribozymes), antisense nucleic acids, 2-5A antisense chimeras, triplex DNA, antisense nucleic acids containing RNA cleaving chemical groups) and methods for their use to down regulate or inhibit the expression of genes ⁇ e.g., NOGO and/or NOGO receptor) capable of progression and or maintenance of CNS injury, spinal cord injury, cerebrovascular accident (CVA, stroke), Alzheimer's disease, dementia, multiple sclerosis (MS), chemotherapy-induced neuropathy, amyotrophic lateral sclerosis (ALS), Parkinson's disease, ataxia, Huntington's disease, Creutzfeldt-Jakob disease, muscular dystrophy, and/or other neurodegenerative disease states which respond to the modulation of NOGO and or NOGO receptor expression.
  • genes ⁇ e.g., NOGO and/or NOGO receptor
  • genes e.g., NOGO and/or
  • the lack of axon regeneration capacity in the adult CNS manifests as a limiting factor in the treatment of CNS injury, cerebrovascular accident (CVA, stroke), chemotherapy- induced neuropathy, and possibly in neurodegenerative diseases such as Alzheimer's disease, dementia, multiple sclerosis (MS), chemotherapy-induced neuropathy, amyotrophic lateral sclerosis (ALS), Parkinson's disease, ataxia, Huntington's disease, Creutzfeldt-Jakob disease, and or muscular dystrophy.
  • Neuron growth inhibition results from physical barriers imposed by glial scars, a lack of neurotrophic factors, and growth-inhibitory molecules associated with myelin. The abrogation of neurite growth inhibition creates the potential to treat conditions for which there is currently no definitive medical intervention.
  • NOGO Genbank Accession No AB020693
  • NOGO-66 receptor Genbank Accession No. AF283463
  • the sequence of human NOGO and NOGO receptor genes are screened for accessible sites using a computer-folding algorithm. Regions of the RNA that do not form secondary folding stmctures and contained potential enzymatic nucleic acid molecule and or antisense binding/cleavage sites are identified. The sequences of these binding/cleavage sites are shown in Tables III- VII.
  • Enzymatic nucleic acid molecule target sites are chosen by analyzing sequences of Human NOGO (Genbank accession No: AB020693) and prioritizing the sites on the basis of folding. Enzymatic nucleic acid molecules are designed that can bind each target and are individually analyzed by computer folding (Christoffersen et al, 1994 J. Mol. Struc Theochem, 311, 273; Jaeger et al, 1989, Proc. Natl. Acad. Sci. USA, 86, 7706) to assess whether the enzymatic nucleic acid molecule sequences fold into the appropriate secondary stmcture. Those enzymatic nucleic acid molecules with unfavorable intramolecular interactions between the binding arms and the catalytic core are eliminated from consideration. As noted below, varying binding arm lengths can be chosen to optimize activity. Generally, at least 5 bases on each arm are able to bind to, or otherwise interact with, the target RNA.
  • Enzymatic nucleic acid molecules and antisense constmcts are designed to anneal to various sites in the RNA message.
  • the binding arms ofthe enzymatic nucleic acid molecules are complementary to the target site sequences described above, while the antisense constmcts are fully complimentary to the target site sequences described above.
  • the enzymatic nucleic acid molecules and antisense constmcts were chemically synthesized. The method of synthesis used followed the procedure for normal RNA synthesis as described above and in Usman et al, (1987 J. Am. Chem.
  • Enzymatic nucleic acid molecules and antisense constmcts are also synthesized from
  • Enzymatic nucleic acid molecules and antisense constmcts are purified by gel electrophoresis using general methods or are purified by high pressure liquid chromatography (HPLC; See Wincott et al, supra; the totality of which is hereby inco ⁇ orated herein by reference) and are resuspended in water.
  • HPLC high pressure liquid chromatography
  • the sequences of the chemically synthesized enzymatic nucleic acid molecules used in this study are shown below in Table III- VII.
  • the sequences of the chemically synthesized antisense constmcts used in this study are complimentary sequences to the Substrate sequences shown below as in Table III-VII.
  • Enzymatic nucleic acid molecules targeted to the human NOGO RNA are designed and synthesized as described above. These enzymatic nucleic acid molecules can be tested for cleavage activity in vitro, for example, using the following procedure.
  • the target sequences and the nucleotide location within the NOGO receptor RNA are given in Tables III-VII.
  • Full-length or partially full-length, internally-labeled target RNA for enzymatic nucleic acid molecule cleavage assay is prepared by in vitro transcription in the presence of [a- 32 p] CTP, passed over a G 50 Sephadex column by spin chromatography and used as substrate RNA without further purification.
  • substrates are 5'-32p-end labeled using T4 polynucleotide kinase enzyme.
  • Assays are performed by pre-warming a 2X concentration of purified enzymatic nucleic acid molecule in enzymatic nucleic acid molecule cleavage buffer (50 mM Tris-HCl, pH 7.5 at 37°C, 10 mM MgCl2) and the cleavage reaction was initiated by adding the 2X enzymatic nucleic acid molecule mix to an equal volume of substrate RNA (maximum of 1-5 nM) that was also pre-warmed in cleavage buffer.
  • enzymatic nucleic acid molecule cleavage buffer 50 mM Tris-HCl, pH 7.5 at 37°C, 10 mM MgCl2
  • assays are carried out for 1 hour at 37 C using a final concentration of either 40 nM or 1 mM enzymatic nucleic acid molecule, i.e., enzymatic nucleic acid molecule excess.
  • the reaction is quenched by the addition of an equal volume of 95% formamide, 20 mM EDTA, 0.05% bromophenol blue and 0.05% xylene cyanol after which the sample is heated to 95 C for 2 minutes, quick chilled and loaded onto a denaturing polyacrylamide gel.
  • Substrate RNA and the specific RNA cleavage products generated by enzymatic nucleic acid molecule cleavage are visualized on an autoradiograph ofthe gel. The percentage of cleavage is determined by Phosphor Imager® quantitation of bands representing the intact substrate and the cleavage products.
  • Nucleic acid molecules targeted to the human NOGO and NOGO receptor RNA are designed and synthesized as described above. These nucleic acid molecules can be tested for cleavage activity in vivo, for example using the procedures described below.
  • the target sequences and the nucleotide location within the NOGO receptor RNA are given in Tables III-VII.
  • nucleic acid molecules of the instant invention directed at the inhibition of NOGO expression can be used in place of mAb FN-1 in studying the inhibition of bNI-220 in cell culture experiments described in detail by Spillmann et al, supra. Criteria used in these experiments include the evaluation of spreading behavior of 3T3 fibroblasts, the neurite outgrowth response of PC 12 cells, and the growth cone motility of chick DRG growth cones.
  • nucleic acid molecules of the instant invention that target NOGO or NOGO receptors can be used to evaluate inhibition of NOGO mediated activity in these cell types using the criteria described above.
  • EN-1 treated animals demonstrate growth of corticospinal axons around the lesion site and into the spinal cord which persist past the longest time point of analysis (12 weeks). Furthermore, both reflex and locomotor function, including the functional recovery of fine motor control, is restored in EN-1 treated animals.
  • a robust animal model as described by Bregman et a I. supra and Z'Graggen et al, supra, can be used to evaluate nucleic acid molecules of the instant invention when used in place of or in conjunction with mAb IN-1 toward use as modulators of neurite growth inhibitor function (eg. NOGO and NOGO receptor) in vivo.
  • the nucleic acids of the present invention can be used to treat a patient having a condition associated with the level of NOGO or NOGO receptor.
  • One method of treatment comprises contacting cells of a patient with a nucleic acid molecule of the present invention, under conditions suitable for said treatment. Delivery methods and other methods of administration have been discussed herein and are commonly known in the art.
  • Particular degenerative and disease states that can be associated with NOGO and NOGO receptor expression modulation include, but are not limited to, CNS injury, specifically spinal cord injury, cerebrovascular accident (CVA, stroke), Alzheimer's disease, dementia, multiple sclerosis (MS), chemotherapy-induced neuropathy, amyotrophic lateral sclerosis (ALS), Parkinson's disease, ataxia, Huntington's disease, Creutzfeldt-Jakob disease, muscular dystrophy, and/or other neurodegenerative disease states which respond to the modulation of NOGO and NOGO receptor expression.
  • CVA cerebrovascular accident
  • MS multiple sclerosis
  • chemotherapy-induced neuropathy amyotrophic lateral sclerosis
  • Parkinson's disease ataxia
  • Huntington's disease Creutzfeldt-Jakob disease
  • muscular dystrophy and/or other neurodegenerative disease states which respond to the modulation of NOGO and NOGO receptor expression.
  • the present body of knowledge in NOGO research indicates the need for methods to assay NOGO activity and for compounds that can regulate NOGO expression for research, diagnostic, and therapeutic use.
  • Other treatment methods comprise contacting cells of a patient with a nucleic acid molecule of the present invention and further comprise the use of one or more drug therapies under conditions suitable for said treatment.
  • monoclonal antibody eg; mAb IN-1
  • growth factors e.g. mAb IN-1
  • antiinflammatory compounds for example methylprednisolone
  • calcium blockers for example GM-1 ganglioside
  • apoptosis inhibiting compounds for example GM-1 ganglioside
  • physical therapies for example treadmill therapy
  • dmg compounds and therapies can be similarly be readily combined with the nucleic acid molecules of the instant invention ⁇ e.g. ribozymes and antisense molecules) are hence within the scope ofthe instant invention.
  • the nucleic acid molecules of this invention can be used as diagnostic tools to examine genetic drift and mutations within diseased cells or to detect the presence of NOGO and/or NOGO receptor RNA in a cell.
  • the close relationship between enzymatic nucleic acid molecule activity and the stmcture of the target RNA allows the detection of mutations in any region of the molecule which alters the base-pairing and three-dimensional stmcture of the target RNA.
  • multiple enzymatic nucleic acid molecules described in this invention one can map nucleotide changes which are important to RNA stmcture and function in vitro, as well as in cells and tissues.
  • Cleavage of target RNAs with enzymatic nucleic acid molecules can be used to inhibit gene expression and define the role (essentially) of specified gene products in the progression of disease. In this manner, other genetic targets can be defined as important mediators ofthe disease. These experiments can lead to better treatment of the disease progression by affording the possibility of combinational therapies ⁇ e.g., multiple enzymatic nucleic acid molecules targeted to different genes, enzymatic nucleic acid molecules coupled with known small molecule inhibitors, or intermittent treatment with combinations of enzymatic nucleic acid molecules and/or other chemical or biological molecules).
  • Other in vitro uses of enzymatic nucleic acid molecules of this invention are well known in the art, and include detection of the presence of mRNAs associated with NOGO-related condition. Such RNA is detected by determining the presence of a cleavage product after treatment with a enzymatic nucleic acid molecule using standard methodology.
  • enzymatic nucleic acid molecules which cleave only wild-type or mutant forms of the target RNA are used for the assay.
  • the first enzymatic nucleic acid molecule is used to identify wild-type RNA present in the sample and the second enzymatic nucleic acid molecule is used to identify mutant RNA in the sample.
  • synthetic substrates of both wild-type and mutant RNA are cleaved by both enzymatic nucleic acid molecules to demonstrate the relative enzymatic nucleic acid molecule efficiencies in the reactions and the absence of cleavage of the "non-targeted" RNA species.
  • the cleavage products from the synthetic substrates also serve to generate size markers for the analysis of wild-type and mutant RNAs in the sample population.
  • each analysis requires two enzymatic nucleic acid molecules, two substrates and one unknown sample which is combined into six reactions.
  • the presence of cleavage products is determined using an RNAse protection assay so that full-length and cleavage fragments of each RNA can be analyzed in one lane of a polyacrylamide gel. It is not absolutely required to quantify the results to gain insight into the expression of mutant RNAs and putative risk of the desired phenotypic changes in target cells.
  • the expression of mRNA whose protein product is implicated in the development of the phenotype is adequate to establish risk.
  • RNA levels are compared qualitatively or quantitatively.
  • the use of enzymatic nucleic acid molecules in diagnostic applications contemplated by the instant invention is more fully described in George et al, US Patent Nos. 5,834,186 and 5,741,679, Shih et al, US Patent No. 5,589,332, Nathan et al, US Patent No 5,871,914, Nathan and Ellington, International PCT publication No. WO 00/24931, and Sullenger et al, International PCT publication No. WO 99/29842.
  • Example 3 Nucleic acid inhibition of EKK-gamma and PKR target RNA
  • the invention features nucleic acid molecules, for example enzymatic nucleic acid molecules, antisense nucleic acid molecules, 2,5-A chimeras, decoys, siRNA, triplex oligonucleotides, siRNA and/or aptamers, and methods to modulate gene expression, for example, genes encoding a member of the IKB kinase EKK complex, such as EKK-alpha (EKKl), EKK-beta (EKK2), or EKK-gamma (IKK ⁇ ) and/or a protein kinase PKR protein, ta particular, the instant invention features nucleic-acid based molecules and methods to modulate the expression of EKK-gamma (EKK ⁇ ) and protein kinase PKR.
  • EKK-alpha EKK-alpha
  • EKK2 EKK-beta
  • IKK ⁇ EKK-gamma
  • IKK ⁇ protein kinase PKR protein
  • the invention features one or more nucleic acid-based molecules and methods that independently or in combination modulate the expression of gene(s) encoding a member of the IKB kinase EKK complex or PKR.
  • the invention features nucleic acid-based molecules and methods that modulate the expression of a member of the IKB kinase EKK complex, for example IKK-alpha (EKK1), EKK-beta (EKK2), or EKK-gamma ( KK ⁇ ) and/or a protein kinase PKR protein, such as EKK-alpha (EKKl) gene (Genbank Accession No.
  • EKK-beta (EKK2) gene for example (Genbank Accession No.AF080158), EKK-gamma (EKK ⁇ ) gene, for example (Genbank Accession No. NM_003639), and protein kinase PKR gene, for example (Genbank Accession No. NM_002759).
  • an enzymatic nucleic acid molecule of the invention comprises a sequence selected from the group consisting of SEQ ED NOs. 7056-7249.
  • an enzymatic nucleic acid molecule of the invention comprises at least one binding arm wherein one or more of said binding arms comprises a sequence complementary to a sequence selected from the group consisting of SEQ ED NOs. 1024-4414.
  • an antisense nucleic acid molecule or siRNA molecule of the invention comprises a sequence complementary to a sequence selected from the group consisting of SEQ ED NOs. 1024-4414.
  • an nucleic acid molecule of the invention is adapted to treat cancer.
  • an enzymatic nucleic acid molecule of the invention has an endonuclease activity to cleave RNA having EKK-gamma or PKR sequence.
  • an enzymatic nucleic acid molecule of the invention is in an taozyme, Zinzyme, G-cleaver, Amberzyme, DNAzyme, or Hammerhead configuration.
  • an taozyme of the invention comprises a sequence complementary to a sequence selected from the group consisting of SEQ ED NOs. 1218-1721 and 3051-3549. In another embodiment, an taozyme of the invention comprises a sequence selected from the group consisting of SEQ ED NOs. 7250-7753 and 9701-10199.
  • a Zinzyme of the invention comprises a sequence complementary to a sequence selected from the group consisting of SEQ ED NOs. 1722-1998 and 3550-3768. In another embodiment, a Zinzyme ofthe invention comprises a sequence selected from the group consisting of SEQ ED NOs 7754-8030 and 10200-10418.
  • an Amberzyme of the invention comprises a sequence selected from the group consisting of SEQ ED NOs 8441-9069 and 11001-11547.
  • a DNAzyme of the invention comprises a sequence selected from the group consisting of SEQ ED NOs 8031-8440 and 10419-11000.
  • a Hammerhead of the invention comprises a sequence complementary to a sequence selected from the group consisting of SEQ ED NOs. 1024-1217 and 2420-3050.
  • a Hammerhead of the invention comprises a sequence selected from the group consisting of SEQ ED NOs 7056-7249 and 9070-9700.
  • a nucleic acid molecule of the invention comprises between 12 and 100 bases complementary to RNA having sequence of IKK-gamma or PKR. In another embodiment, a nucleic acid molecule of the invention comprises between 14 and 24 bases complementary to RNA having sequence of EKK-gamma or PKR.
  • a nucleic acid molecule of the invention is chemically synthesized.
  • a nucleic acid molecule or antisense nucleic acid molecule of the invention comprises at least one 2'-sugar modification, at least one nucleic acid base modification, or at least one phosphate backbone modification.
  • the invention features a mammalian cell, for example a human cell, including an enzymatic nucleic acid molecule ofthe invention.
  • the present invention features method of down-regulating PKR activity in a cell, comprising contacting the cell with a nucleic acid molecule of the invention, under conditions suitable for down-regulating of PKR activity.
  • the present invention also features method of treatment of a patient having a condition associated with the level of PKR, comprising contacting cells of the patient with a nucleic acid molecule ofthe invention under conditions suitable for the treatment.
  • the present invention features method of down-regulating EKK-gamma activity in a cell, comprising contacting the cell with a nucleic acid molecule of the invention, under conditions suitable for down-regulating of EKK-gamma activity.
  • the present invention also features method of treatment of a patient having a condition associated with the level of EKK-gamma, comprising contacting cells of the patient with the nucleic acid molecule ofthe invention, under conditions suitable for the treatment.
  • a method of treatment of the invention comprises the use of one or more dmg therapies under conditions suitable for said treatment.
  • the present invention features method of cleaving RNA comprising a sequence of PKR gene comprising contacting an enzymatic nucleic acid molecule of the invention with the RNA of a PKR gene under conditions suitable for the cleavage.
  • the present invention also features method of cleaving RNA comprising a sequence of EKK-gamma gene comprising contacting an enzymatic nucleic acid molecule ofthe invention with the RNA of an EKK-gamma gene under conditions suitable for the cleavage.
  • a method of cleavage ofthe invention is carried out in the presence of a divalent cation, for example Mg2+.
  • a nucleic acid molecule of the invention comprises a cap stmcture, wherein the cap stmcture is at the 5 '-end, or 3 '-end, or both the 5 '-end and the 3'- end, for example a 3',3'-linked or 5',5'-linked deoxyabasic derivative.
  • the present invention also features an expression vector comprising a nucleic acid sequence encoding at least one nucleic acid molecule the invention in a manner which allows expression ofthe nucleic acid molecule.
  • the invention features a mammalian cell, for example a human cell, including an expression vector contemplated by the invention.
  • an expression vector of the invention further comprises a sequence for a nucleic acid molecule complementary to the RNA of a subunit of EKK-gamma or PKR.
  • an expression vector of the invention comprises a nucleic acid sequence encoding two or more nucleic acid molecules, which can be the same or different.
  • the present invention also features a method for treatment of cancer, for example breast cancer, lung cancer, prostate cancer, colorectal cancer, brain cancer, esophageal cancer, stomach cancer, bladder cancer, pancreatic cancer, cervical cancer, head and neck cancer, ovarian cancer, melanoma, lymphoma, glioma, or multidmg resistant cancer, comprising administering to a patient a nucleic acid molecule of the invention under conditions suitable for said treatment.
  • cancer for example breast cancer, lung cancer, prostate cancer, colorectal cancer, brain cancer, esophageal cancer, stomach cancer, bladder cancer, pancreatic cancer, cervical cancer, head and neck cancer, ovarian cancer, melanoma, lymphoma, glioma, or multidmg resistant cancer
  • a nucleic acid molecule of the invention comprises at least five ribose residues, at least ten 2'-O-methyl modifications, and a 3'- end modification such as a 3 '-3' inverted abasic moiety, and/or phosphorothioate linkages on at least three of the 5' terminal nucleotides.
  • other dmg therapies contemplated by the invention include monoclonal antibodies, EKK-gamma or PKR-specific inhibitors, chemotherapy, or radiation therapy.
  • Specific chemotherapy contemplated by the invention include paclitaxel, docetaxel, cisplatin, methotrexate, cyclophosphamide, doxombin, fluorouracil carboplatin, edatrexate, gemcitabine, or vinorelbine.
  • the invention also features a method for treatment of an inflammatory disease, for example rheumatoid arthritis, restenosis, asthma, Crohn's disease, diabetes, obesity, autoimmune disease, lupus, multiple sclerosis, transplant/graft rejection, gene therapy applications, ischemia/reperfusion injury, glomemlonephritis, sepsis, allergic airway inflammation, inflammatory bowel disease, or infection, comprising the step of administering to a patient a nucleic acid molecule of the invention under conditions suitable for the treatment.
  • an inflammatory disease for example rheumatoid arthritis, restenosis, asthma, Crohn's disease, diabetes, obesity, autoimmune disease, lupus, multiple sclerosis, transplant/graft rejection, gene therapy applications, ischemia/reperfusion injury, glomemlonephritis, sepsis, allergic airway inflammation, inflammatory bowel disease, or infection.
  • the present invention features pharmaceutical compositions comprising the nucleic acid molecules ofthe invention in a pharmaceutically acceptable carrier.
  • the invention also features a method of administering to a cell, such as mammalian cell (e.g. human cell), where the cell can be in culture or in a mammal, such as a human, an enzymatic nucleic acid molecule or antisense molecule of the instant invention, comprising contacting the cell with the nucleic acid molecule under conditions suitable for such administration.
  • a delivery reagent for example a lipid, cationic lipid, phospholipid, or liposome.
  • the nucleic acid molecules that target specific sites in EKK-gamma or PKR-specific RNAs represent a therapeutic approach to treat a variety of inflammatory-related diseases and conditions, including but not limited to rheumatoid arthritis, restenosis, asthma, Crohn's disease, incontinentia pigmenti, diabetes, obesity, autoimmune disease, lupus, multiple sclerosis, transplant/graft rejection, gene therapy applications, ischemia/reperfusion injury (CNS and myocardial), glomemlonephritis, sepsis, allergic airway inflammation, inflammatory bowel disease, infection, and any other inflammatory disease or condition which respond to the modulation of EKK-gamma or PKR function.
  • rheumatoid arthritis restenosis
  • asthma Crohn's disease
  • incontinentia pigmenti diabetes
  • obesity autoimmune disease
  • lupus multiple sclerosis
  • transplant/graft rejection transplant/graft rejection
  • gene therapy applications ischemia/reperfusion injury (CN
  • PKR-specific RNAs also represent a therapeutic approach to treat a variety of cancers, including but not limited to breast, lung, prostate, colorectal, brain, esophageal, bladder, pancreatic, cervical, head and neck, and ovarian cancer, melanoma, lymphoma, glioma, multidmg resistant cancers, and/or other cancers which respond to the modulation of EKK- gamma or PKR function.
  • a nucleic acid molecule that modulates, for example, down- regulates EKK-gamma or PKR expression comprises between 12 and 100 bases complementary to a RNA molecule of EKK-gamma or PKR.
  • a nucleic acid molecule that modulates, for example EKK-gamma or PKR expression comprises between 14 and 24 bases complementary to a RNA molecule of EKK-gamma or PKR.
  • Nucleic acid-based inhibitors of EKK-gamma or PKR function are useful for the prevention and/or treatment of cancers and cancerous conditions such as breast, lung, prostate, colorectal, brain, esophageal, bladder, pancreatic, cervical, head and neck, and ovarian cancer, melanoma, lymphoma, glioma, multidmg resistant cancers, and any other diseases or conditions that are related to or will respond to the levels of EKK-gamma or PKR in a cell or tissue, alone or in combination with other therapies.
  • cancers and cancerous conditions such as breast, lung, prostate, colorectal, brain, esophageal, bladder, pancreatic, cervical, head and neck, and ovarian cancer, melanoma, lymphoma, glioma, multidmg resistant cancers, and any other diseases or conditions that are related to or will respond to the levels of EKK-gamma or PKR in a cell or tissue, alone or in combination
  • Nucleic acid-based inhibitors of EKK-gamma or PKR function are also useful for the prevention and/or treatment of inflammatory related diseases and conditions, including but not limited to rheumatoid arthritis, restenosis, asthma, Crohn's disease, incontinentia pigmenti, diabetes, obesity, autoimmune disease, lupus, multiple sclerosis, transplant/graft rejection, gene therapy applications, ischemia/reperfusion injury (CNS and myocardial), glomemlonephritis, sepsis, allergic airway inflammation, inflammatory bowel disease, infection, and any other inflammatory disease or condition which respond to the modulation of EKK-gamma or PKR function.
  • inflammatory related diseases and conditions including but not limited to rheumatoid arthritis, restenosis, asthma, Crohn's disease, incontinentia pigmenti, diabetes, obesity, autoimmune disease, lupus, multiple sclerosis, transplant/graft rejection, gene therapy applications, ischemia/reperfusion injury (CNS
  • the described nucleic acid molecules can be used in combination with other known treatments to treat conditions or diseases discussed above.
  • the described molecules can be used in combination with one or more known therapeutic agents to treat breast, lung, prostate, colorectal, brain, esophageal, bladder, pancreatic, cervical, head and neck, and ovarian cancer, melanoma, lymphoma, glioma, multidmg resistant cancers, rheumatoid arthritis, restenosis, asthma, Crohn's disease, diabetes, incontinentia pigmenti, obesity, autoimmune disease, lupus, multiple sclerosis, transplant/graft rejection, gene therapy applications, ischemia/reperfusion injury (CNS and myocardial), glomemlonephritis, sepsis, allergic airway inflammation, inflammatory bowel disease, infection, and any other cancerous disease or inflammatory disease or condition which respond to the modulation of
  • the sequence of human EKK-gamma or PKR genes are screened for accessible sites using a computer- folding algorithm. Regions of the RNA that do not form secondary folding stmctures and contained potential enzymatic nucleic acid molecule and/or antisense binding cleavage sites are identified. The sequences of these binding/cleavage sites are shown in Tables VIII-XVIII.
  • Enzymatic nucleic acid molecule target sites are chosen by analyzing sequences of Human EKK-gamma (Genbank accession No: NM 003639) and PKR (Genbank accession No: NM_002759) and prioritizing the sites on the basis of folding. Enzymatic nucleic acid molecules are designed that can bind each target and are individually analyzed by computer folding (Christoffersen et al, 1994 J. Mol. Struc. Theochem, 311, 273; Jaeger et al, 1989, Proc Natl. Acad. Sci. USA, 86, 7706) to assess whether the enzymatic nucleic acid molecule sequences fold into the appropriate secondary stmcture.
  • binding arm lengths can be chosen to optimize activity. Generally, at least 5 bases on each arm are able to bind to, or otherwise interact with, the target RNA.
  • Enzymatic nucleic acid molecules and antisense constmcts are designed to anneal to various sites in the RNA message.
  • the binding arms ofthe enzymatic nucleic acid molecules are complementary to the target site sequences described above, while the antisense constructs are fully complementary to the target site sequences described above.
  • the enzymatic nucleic acid molecules and antisense constmcts were chemically synthesized. The method of synthesis used followed the procedure for normal RNA synthesis as described above and in Usman et al, (1987 J. Am. Chem.
  • Enzymatic nucleic acid molecules and antisense constructs are also synthesized from DNA templates using bacteriophage T7 RNA polymerase (Milligan and Uhlenbeck, 1989, Methods Enzymol. 180, 51). Enzymatic nucleic acid molecules and antisense constmcts are purified by gel electrophoresis using general methods or are purified by high pressure liquid chromatography (HPLC; See Wincott et al, supra; the totality of which is hereby inco ⁇ orated herein by reference) and are resuspended in water. The sequences of the chemically synthesized enzymatic nucleic acid molecules used in this study are shown below in Table XVIII. The sequences of the chemically synthesized antisense constmcts used in this study are complementary sequences to the Substrate sequences shown below as in Tables VIII-XVIII.
  • Enzymatic nucleic acid molecules targeted to the human IKK-gamma or PKR RNA are designed and synthesized as described above. These enzymatic nucleic acid molecules can be tested for cleavage activity in vitro, for example, using the following procedure.
  • the target sequences and the nucleotide location within the EKK-gamma or PKR RNA are given in
  • Full-length or partially full-length, internally-labeled target RNA for enzymatic nucleic acid molecule cleavage assay is prepared by in vitro transcription in the presence of [a- 32 p] CTP, passed over a G 50 Sephadex column by spin chromatography and used as substrate RNA without further purification.
  • substrates are 5'-32p-end labeled using T4 polynucleotide kinase enzyme.
  • Assays are performed by pre-warming a 2X concentration of purified enzymatic nucleic acid molecule in enzymatic nucleic acid molecule cleavage buffer (50 mM Tris-HCl, pH 7.5 at 37°C, 10 mM MgCb) and the cleavage reaction was initiated by adding the 2X enzymatic nucleic acid molecule mix to an equal volume of substrate RNA (maximum of 1-5 nM) that was also pre-warmed in cleavage buffer.
  • enzymatic nucleic acid molecule cleavage buffer 50 mM Tris-HCl, pH 7.5 at 37°C, 10 mM MgCb
  • assays are carried out for 1 hour at 37 C using a final concentration of either 40 nM or 1 mM enzymatic nucleic acid molecule, i.e., enzymatic nucleic acid molecule excess.
  • the reaction is quenched by the addition of an equal volume of 95%) formamide, 20 mM
  • EDTA 0.05%) bromophenol blue and 0.05% xylene cyanol after which the sample is heated o to 95 C for 2 minutes, quick chilled and loaded onto a denaturing polyacrylamide gel.
  • Substrate RNA and the specific RNA cleavage products generated by enzymatic nucleic acid molecule cleavage are visualized on an autoradiograph of the gel. The percentage of cleavage is determined by Phosphor Imager® quantitation of bands representing the intact substrate and the cleavage products.
  • Nucleic acid molecules targeted to the human EKK-gamma or PKR RNA are designed and synthesized as described above. These nucleic acid molecules can be tested for cleavage activity in vivo, for example using the procedures described below.
  • the target sequences and the nucleotide location within the EKK-gamma or PKR RNA are given in Tables VIII- XVIII.
  • Phenotypic endpoints include inhibition of cell proliferation, apoptosis assays and reduction of EKK- gamma or PKR protein expression, or a decrease in NFKB expression. Since IKK-gamma and PKR are both involved in the induction of NFKB, NFKB can be used as a surrogate marker in cell culture, animal, and clinical studies.
  • a proliferation endpoint for cell culture assays is preferably used as a primary screen. There are several methods by which this endpoint can be measured. Following treatment of cells with nucleic acid molecules, cells are allowed to grow (typically 5 days) after which either the cell viability, the inco ⁇ oration of [ 3 H] thymidine into cellular DNA and/or the cell density can be measured.
  • the assay of cell density is very straightforward and can be performed in a 96-well format using commercially available fluorescent nucleic acid stains (such as Syto® 13 or CyQuant®). The assay using CyQuant® is described herein
  • EKK-gamma or PKR RNA and/or EKK-gamma or PKR protein expression can be evaluated. Alternately, a decrease in the level of NFKB RNA can be evaluated.
  • Cell types that express/over-express NFKB include HeLa, macrophages, peripheral blood lymphocytes, hepatocytes, fibroblasts, endothelial cells and epithelial cells, ta culture, these cells can be stimulated to express/over-express NFKB by addition of TNF-alpha PMA or IL-1-beta to the culture medium. Some of these cell types also can respond with a similar activation of NFKB following LPS treatment. Activation of NFKB in cultured cells can be evaluated by electrophoretic mobility shift assay (EMSA). Delineation of alterations in the subunits can be determined by Western blot.
  • EMSA electrophoretic mobility shift assay
  • a useful cell culture system in evaluating NFKB modulation is human colonic epithelial cells.
  • One suitable cell line is SW620 colon carcinoma cells (CCL227). These cells respond to stimulation with TNF-alpha, LPS and/or EL- 1 -beta with an increase in NFKB activation.
  • SW620 cells are grown in MEM supplemented with 10%> heat-inactivated FBS and glutamine (2 mmol/L).
  • TNF-alpha dose-response curves in these cells are determined by incubating cells with various concentrations of recombinant human TNF-alpha (Sigma Chemical Co.). Maximal DNA binding activity induction can occur with 150U/ml TNF-alpha in the culture medium. Induction is typically evident within 10 minutes of treatment with TNF-alpha reaches a peak at one hour post-treatment and persists for up to 4 hours post-treatment.
  • the primary readout can be NFKB DNA activity in nuclear extracts of SW620 cells as determined by electrophoretic mobility shift assays (EMSA).
  • TNF-alpha inhibition of EKK-gamma, PKR, or NFKB activation is evaluated using specific and non-specific inhibitors of activation, sulfasalazine and steroids, respectively.
  • Cells are incubated with inhibitors or control media for 30 minutes prior to stimulation with TNF-alpha
  • Nuclear extracts are prepared and evaluated for DNA binding activity by EMSA.
  • EMSA Once the activity of positive controls has been established, enzymatic nucleic acids targeting the EKK-gamma or PKR are evaluated in this system.
  • Supershift assays using polyclonal antibodies against the NFKB or PKR protein subunits can be performed to confirm down-regulation of NFKB.
  • SW620 cells can be transfected with the 3xIg-kappa-B-Luc reporter construct 18 hours before challenge with TNF-alpha, LPS or PMA.
  • the readout for this assay is luciferase activity.
  • Test compounds are applied 17.5 hours after transfection (30 minutes before challenge).
  • Cells are harvested 24 hours after challenge and relative changes in luciferase activity is used as the endpoint.
  • the activation of NFKB can be visualized fluorescently.
  • Inactive NFKB heterodimers are held in the cytoplasm by inhibitory proteins. Once activated, the free heterodimers translocate to the nucleus.
  • the relative change in cytopiasmic versus nuclear fluorescence can indicate the degree of NFKB activation.
  • Cells can be grown on chamber slides, treated with TNF-alpha with and without test compounds), and the location of the NFKB subunit can be determined by immunofluorescence using a FITC-labeled antibody to NFKB.
  • Tumor cell lines are characterized to establish their growth curves in mice. These cell lines are implanted into both nude and SCED mice and primary tumor volumes are measured 3 times per week. Growth characteristics of these tumor lines using a Matrigel implantation format can also be established. The use of other cell lines that have been engineered to express high levels of NFKB can also be used in the described studies.
  • the tumor cell line(s) and implantation method that supports the most consistent and reliable tumor growth is used in animal studies testing the lead IKK-gamma or PKR nucleic acid(s). Nucleic acids are administered by daily subcutaneous injection or by continuous subcutaneous infusion from Alzet mini osmotic pumps beginning 3 days after tumor implantation and continuing for the duration of the study. Group sizes of at least 10 animals are employed.
  • Efficacy is determined by statistical comparison of tumor volume of nucleic acid-treated animals to a control group of animals treated with saline alone. Because the growth of these tumors is generally slow (45-60 days), an initial endpoint is the time in days it takes to establish an easily measurable primary tumor (i.e. 50-100 mm 3 ) in the presence or absence of nucleic acid treatment.
  • mice are euthanized by CO2 asphyxiation, small intestines excised and gross pathologic findings ranked according to the following criteria: 0, normal ; 1, minimal abnormalities, slight thickening of the small intestine, no adhesions; 2, obvious thickening of small intestine with 1 adhesion; 3, obvious thickening of small intestine with 2 or 3 adhesions; 4, massive adhesions to the extent that the intestine cannot be separated, contents primarily fluid; 5, severe peritonitis resulting in death.
  • a 10-cm portion of the most affected region of the small intestine is weighed, placed in 10%) neutral buffered formalin and submitted for histopatho logic evaluation.
  • the 10 cm portion of gut from each animal is cut into five equal sections. Transverse and longitudinal sections of each portion are cut and stained with hematoxylin and eosin. All slides are read in a blinded fashion and each section is scored for necrosis (%> area of involvement) and inflammatory response according to the following scale:
  • the scores for each ofthe five sections are averaged for necrosis and for inflammation.
  • cancer patients can be pre-screened for elevated NFKB prior to admission to initial clinical trials testing an anti-EKK- gamma or PKR nucleic acid.
  • Initial NFKB levels can be determined (by ELISA) from tumor biopsies or resected tumor samples. During clinical trials, it can be possible to monitor circulating NFKB protein by ELISA. Evaluation of serial blood/serum samples over the course of the anti-EKK-gamma or PKR nucleic acid treatment period could be useful in determining early indications of efficacy.
  • Applicant has designed and synthesized several nucleic acid molecules targeted against EKK-gamma or PKR RNA. These nucleic acid molecules can be tested in cell proliferation and RNA reduction assays described herein.
  • a model proliferation assay can be done using a cell-plating density of 2,000-10,000 cells/well in 96-well plates and at least 2 cell doublings over a 5-day treatment period.
  • Cells used in proliferation studies can be, for example, were either lung or ovarian cancer cells (A549 and SKON-3 cells respectively).
  • the FEPS fluoro-imaging processing system
  • This method allows for cell density measurements after nucleic acids are stained with CyQuant® dye, and has the advantage of accurately measuring cell densities over a very wide range 1,000- 100,000 cells/well in 96-well format.
  • Enzymatic nucleic acid molecules (50-200 nM) are delivered in the presence of cationic lipid at 2.5-5.0 ⁇ g/mL and inhibition of proliferation can be determined on day 5 post-treatment.
  • R ⁇ A is harvested 24 hours post-treatment using the Qiagen R ⁇ easy® 96 procedure.
  • Real time RT-PCR (TaqMan® assay) is performed on purified R ⁇ A samples using separate primer/probe sets specific for target EKK-gamma or PKR R ⁇ A.
  • Particular degenerative and disease states that can be associated with EKK-gamma or PKR expression modulation include but are not limited to cancerous and or inflammatory diseases and conditions such as breast, lung, prostate, colorectal, brain, esophageal, bladder, pancreatic, cervical, head and neck, and ovarian cancer, melanoma, lymphoma, glioma, multidmg resistant cancers, rheumatoid arthritis, restenosis, asthma, Crohn's disease, diabetes, obesity, autoimmune disease, lupus, multiple sclerosis, transplant/graft rejection, gene therapy applications, ischemia/reperfusion injury (C ⁇ S and myocardial), glomemlonephritis, sepsis, allergic airway inflammation, inflammatory bowel disease, infection, incontinentia pigmenti and any other diseases or conditions that are related to or respond to the levels of EKK-gamma or PKR in a cell or tissue.
  • nucleic acid molecules ⁇ e.g. ribozymes and antisense molecules
  • chemotherapies that can be combined with nucleic acid molecules of the instant invention include various combinations of cytotoxic dmgs to kill cancer cells.
  • dmgs include but are not limited to paclitaxel (Taxol), docetaxel, cisplatin, methotrexate, cyclophosphamide, doxombin, fluorouracil carboplatin, edatrexate, gemcitabine, vinorelbine etc.
  • paclitaxel Taxol
  • docetaxel cisplatin
  • methotrexate cyclophosphamide
  • doxombin fluorouracil carboplatin
  • edatrexate gemcitabine
  • gemcitabine vinorelbine
  • the nucleic acid molecules of this invention can be used as diagnostic tools to examine genetic drift and mutations within diseased cells or to detect the presence of EKK-gamma or PKR RNA in a cell.
  • the close relationship between enzymatic nucleic acid molecule activity and the stmcture of the target RNA allows the detection of mutations in any region of the molecule which alters the base-pairing and three- dimensional stmcture ofthe target RNA.
  • By using multiple enzymatic nucleic acid molecules described in this invention one can map nucleotide changes which are important to RNA stmcture and function in vitro, as well as in cells and tissues.
  • Cleavage of target RNAs with enzymatic nucleic acid molecules can be used to inhibit gene expression and define the role (essentially) of specified gene products in the progression of disease, ta this manner, other genetic targets can be defined as important mediators of the disease.
  • combinational therapies e.g., multiple enzymatic nucleic acid molecules targeted to different genes, enzymatic nucleic acid molecules coupled with known small molecule inhibitors, or intermittent treatment with combinations of enzymatic nucleic acid molecules and/or other chemical or biological molecules).
  • enzymatic nucleic acid molecules of this invention include detection of the presence of mRNAs associated with EKK-gamma or PKR-related condition. Such RNA is detected by determining the presence of a cleavage product after treatment with an enzymatic nucleic acid molecule using standard methodology.
  • enzymatic nucleic acid molecules which cleave only wild-type or mutant forms of the target RNA are used for the assay.
  • the first enzymatic nucleic acid molecule is used to identify wild-type RNA present in the sample and the second enzymatic nucleic acid molecule is used to identify mutant RNA in the sample.
  • synthetic substrates of both wild-type and mutant RNA are cleaved by both enzymatic nucleic acid molecules to demonstrate the relative enzymatic nucleic acid molecule efficiencies in the reactions and the absence of cleavage of the "non-targeted" RNA species.
  • the cleavage products from the synthetic substrates also serve to generate size markers for the analysis of wild-type and mutant RNAs in the sample population.
  • each analysis requires two enzymatic nucleic acid molecules, two substrates and one unknown sample which is combined into six reactions.
  • the presence of cleavage products is determined using an RNAse protection assay so that full-length and cleavage fragments of each RNA can be analyzed in one lane of a polyacrylamide gel. It is not absolutely required to quantify the results to gain insight into the expression of mutant RNAs and putative risk of the desired phenotypic changes in target cells.
  • RNA whose protein product is implicated in the development of the phenotype ⁇ i.e., EKK-gamma or PKR is adequate to establish risk. If probes of comparable specific activity are used for both transcripts, then a qualitative comparison of RNA levels will be adequate and will decrease the cost ofthe initial diagnosis. Higher mutant form to wild-type ratios are correlated with higher risk whether RNA levels are compared qualitatively or quantitatively.
  • the use of enzymatic nucleic acid molecules in diagnostic applications contemplated by the instant invention is more fully described in George et al, US Patent Nos. 5,834,186 and 5,741,679, Shih et al, US Patent No.
  • sequence-specific enzymatic nucleic acid molecules of the instant invention can have many of the same applications for the study of RNA that DNA restriction endonucleases have for the study of DNA (Nathans et al, 1975 Ann. Rev. Biochem. 44:273).
  • the pattern of restriction fragments can be used to establish sequence relationships between two related RNAs, and large RNAs can be specifically cleaved to fragments of a size more useful for study.
  • the ability to engineer sequence specificity of the enzymatic nucleic acid molecule is ideal for cleavage of RNAs of unknown sequence.
  • Applicant has described the use of nucleic acid molecules to down-regulate gene expression of target genes in bacterial, microbial, fungal, viral, and eukaryotic systems including plant, or mammalian cells.
  • Reaction mechanism attack by the 3'-OH of guanosine to generate cleavage products with 3' -OH and 5' -guanosine.
  • RNAse P RNA Ml RNA
  • Size -290 to 400 nucleotides.
  • RNA portion of a ubiquitous ribonucleoprotein enzyme • RNA portion of a ubiquitous ribonucleoprotein enzyme.
  • Reaction mechanism possible attack by M 2+ -OH to generate cleavage products with 3'-OH and 5' -phosphate.
  • RNAse P is found throughout the prokaryotes and eukaryotes.
  • the RNA subunit has been sequenced from bacteria, yeast, rodents, and primates.
  • Reaction mechanism 2' -OH of an internal adenosine generates cleavage products with 3'-OH and a "lariat" RNA containing a 3' -5' and a 2' -5' branch point.
  • Reaction mechanism attack by 2' -OH 5' to the scissile bond to generate cleavage products with 2' ,3' -cyclic phosphate and 5' -OH ends.
  • Reaction mechanism attack by 2' -OH 5' to the scissile bond to generate cleavage products with 2',3'-cyclic phosphate and 5' -OH ends.
  • Reaction mechanism attack by 2' -OH 5' to the scissile bond to generate cleavage products with 2',3'-cyclic phosphate and 5' -OH ends.
  • RNA RNA as the infectious agent.
  • Ligation activity (in addition to cleavage activity) makes ribozyme amenable to engineering through in vitro selection [ xxxv ]
  • HDV Hepatitis Delta Virus
  • Folded ribozyme contains a pseudoknot structure [ x1 ].
  • Reaction mechanism attack by 2' -OH 5' to the scissile bond to generate cleavage products with 2' ,3' -cyclic phosphate and 5' -OH ends.
  • Circular form of HDV is active and shows increased nuclease stability [ xh ] I . Michel, Francois; Westhof, Eric. Slippery substrates. Nat. Struct. Biol. (1994), 1(1), 5-7.
  • a group II intron RNA is a catalytic component of a DNA endonuclease involved in intron mobility.
  • Cell Cell (Cambridge, Mass.) (1995), 83(4), 529-38.
  • xxl Griffin, Edmund A., Jr.; Qin, Zhifeng; Michels, Williams J., Jr.; Pyle, Anna Marie.
  • Group II intron ribozymes that cleave DNA and RNA linkages with similar efficiency, and lack contacts with substrate 2'- hydroxyl groups. Chem. Biol. (1995), 2(11), 761-70. x " . Michel, Francois; Ferat, Jean Luc. Structure and activities of group II introns. Annu. Rev. Biochem.
  • XXXIV Joint, Simpson; Berzal-Herranz, Alfredo; Chowrira, Bharat M.; Butcher, Samuel E.. Substrate selection rules for the hairpin ribozyme determined by in vitro selection, mutation, and analysis of mismatched substrates. Genes Dev. (1993), 7(1), 130-8. XXV . Berzal-Herranz, Alfredo; Joseph, Simpson; Burke, John M.. In vitro selection of active hairpin ribozymes by sequential RNA-catalyzed cleavage and ligation reactions. Genes Dev. (1992), 6(1), 129-34. xxxvi Hegg, Lisa A.; Fedor, Martha J..
  • AAACGCCU A GCUGCCAA 68 UUGGCAGC CUGAUGAGGCCGUUAGGCCGAA AGGCGUUU 5551
  • Underlined region can be any X sequence or linker, as described herein.

Abstract

The present invention relates to nucleic acid molecules, including antisense, enzymatic nucleic acid molecules, and RNA interference molecules, such as hammerhead ribozymes, DNAzymes, allozymes, siRNA, decoys and antisense, which modulate the expression of prostaglandin D2 (PTGDS), prostaglandin D2 receptor (PTGDR), adenosine receptor, NOGO and NOGO receptor, and IKK genes, such as IKK-gamma, IKK-alpha, or IKK-beta, and PKR genes.

Description

DESCRIPTION
MODULATION OF GENE EXPRESSION ASSOCIATED WITH
INFLAMMATION PROLIFERATION AND NEURITE OUTGROWTH. USING
NUCLEIC ACID BASED TECHNOLOGIES
Background Of The Invention
This patent application claims priority from USSN (09/827,395), filed April 5, 2001, entitled "METHOD AND REAGENT FOR THE INHIBITION OF NOGO AND NOGO RECEPTOR GENES", which is a continuation-in-part of Blatt, USSN (09/780,533) filed February 9, 2001 , entitled "METHOD AND REAGENT FOR THE INHIBITION OF NOGO GENE" which claims priority from Blatt, USSN (60/181,797), filed February 11, 2000, entitled "METHOD AND REAGENT FOR THE INHIBITION OF NOGO GENE". This patent application also claims priority from USSN (60/294,412), filed May 29, 2001, entitled "ENZYMATIC NUCLEIC ACID TREATMENT OF DISEASES OR CONDITIONS RELATED TO LEVELS OF D K-GAMMA AND PKR", and USSN (60/315,315), filed August 28, 2001, entitled "METHOD AND REAGENT FOR THE TREATMENT OF ASTHMA AND ALLERGIC CONDITIONS". These applications are hereby incorporated by reference herein in their entirety including the drawings.
The present invention provides compounds, compositions, and methods for the study, diagnosis, and treatment of conditions relating to the expression of NOGO and NOGO receptor genes. In particular, the invention provides nucleic acid molecules that are used to modulate the expression of NOGO and NOGO receptor gene products. The present invention further relates to therapeutic compositions and methods for the treatment or diagnosis of diseases or conditions related to IKK gamma (D KG) and PKR levels, such as cancer, inflammatory, and autoimmune diseases and/or disorders. In addition, the present invention also relates to therapeutic compositions and methods for the treatment or diagnosis of diseases or conditions related to allergic response. Specifically, the invention provides compositions and methods for the treatment of diseases or conditions related to levels of factors involved in allergic conditions such as asthma, for example prostaglandin D2 receptor (PTGDR), prostaglandin D2 synthetase (PTGDS) and adenosine Al receptor (ADORA1).
The discussions that follow are not meant to be complete and are provided only to assist understanding the invention that follows. The summary is not an admission that any of the work described below is prior art to the claimed invention.
The following is a brief description of the current understanding of NOGO and NOGO receptors. The ceased growth of neurons following development has severe implications for lesions of the central nervous system (CNS) caused by neurodegenerative disorders and traumatic accidents. Although CNS neurons have the capacity to rearrange their axonal and dendritic foci in the developed brain, the regeneration of severed CNS axons spanning distance does not exist. Axonal growth following CNS injury is limited by the local tissue environment rather than intrinsic factors, as indicated by transplantation experiments (Richardson et al, 1980, Nαtwre, 284, 264-265). Νon-neuronal glial cells of the CΝS, including oligodendrocytes and astrocytes, have been shown to inhibit the axonal growth of dorsal root ganglion neurons in culture (Schwab and Thoenen,1985, J Neurosci., 5, 2415- 2423). Cultured dorsal root ganglion cells can extend their axons across glial cells from the peripheral nervous system, (ie; Schwann cells), but are inhibited by oligodendrocytes and myelin ofthe CΝS (Schwab and Caroni, 1988, J. Neurosci., 8, 2381-2393).
The non-conducive properties of CΝS tissue in adult vertebrates is thought to result from the existence of inhibitory factors rather than the lack of growth factors. The identification of proteins with neurite outgrowth inhibitory or repulsive properties include ΝI- 35, ΝI-250 (Caroni and Schwab, 1988, Neuron, 1, 85-96), myelin-associated glycoprotein (Genbank Accession No M29273), tenascin-R (Genbank Accession No X98085), and NG-2 (Genbank Accession No X61945). Monoclonal antibodies (mAb IN-1) raised against NI- 35/250 have been shown to partially neutralize the growth inhibitory effect of CNS myelin and oligodendrocytes. IN-1 treatment in vivo has resulted in long distance fiber regeneration in lesioned adult mammalian CNS tissue (Weibel et al., 1994, Brain Res., 642, 259-266). Additionally, IN-1 treatment in vivo has resulted in the recovery of specific reflex and locomotor functions after spinal cord injury in adult rats (Bregman et al., 1995, Nature, 378, 498-501).
Recently, the cloning of NOGO-A (Genbank Accession No AJ242961), the rat complementary DNA encoding NI-220/250 has been reported (Chen et al., 2000, Nature, 403, 434-439). The NOGO gene encodes at least three major protein products (NOGO-A, NOGO-B, and NOGO-C) resulting from both alternative promoter usage and alternative splicing. Recombinant NOGO-A inhibits neurite outgrowth from dorsal root ganglia and the spreading of 3T3 firboblasts. Monoclonal antibody IN-1 recognizes NOGO-A and neutralizes NOGO-A inhibition of neuronal growth in vitro. Evidence supports the proposal that NOGO-A is the previously described rat NI-250 since NOGO-A contains all six peptide sequences obtained from purified bNI-220, the bovine equivalent of rat NI-250 (Chen et al supra).
Prinjha et al., 2000, Nature, 403, 383-384, report the cloning ofthe human NOGO gene which encodes three different NOGO isoforms that are potent inhibitors of neurite outgrowth.
Using oligonucleotide primers to amplify and clone overlapping regions of the open reading frame of NOGO cDNA, Phrinjha et al., supra identified three forms of cDNA clone corresponding to the three protein isoforms. The longest ORF of 1,192 amino acids corresponds to NOGO-A (Accession No. AJ251383). An intermediate-length splice variant that lacks residues 186-1,004 corresponds to NOGO-B (Accession No. AJ251384). The shortest splice variant, NOGO-C (Accession No. AJ251385), appears to be the previously described rat vp20 (Accession No. AF051335) and foocen-s (Accession No. AF132048), and also lacks residues 186-1,004. According to Prinjha et al, supra, the NOGO amino-terminal region shows no significant homology to any known protein, while the carboxy-terminal tail shares homology with neuroendocrine-specific proteins and other members of the reticulon gene family. In addition, the carboxy-terminal tail contains a consensus sequence that may serve as an endoplasmic-reticulum retention region. Based on the NOGO protein sequence, Prinjha et al, supra, postulate NOGO to be a membrane associated protein comprising a putative large extracellular domain of 1,024 residues with seven predicted N-linked glycosylation sites, two or three transmembrane domains, and a short carboxy-terminal region of 43 residues.
Grandpre et al, 2000, Nature, also report the identification of NOGO as a potent inhibitor of axon regeneration. The 4.1 kilobase NOGO human cDNA clone identified by Grandpre et al, supra, KIAA0886, is homologous to a cDNA derived from a previous effort to sequence random high molecular-weight brain derived cDNAs (Nagase et al, 1998, DNA Res., 31, 355-364). This cDNA clone encodes a protein that matches all six of the peptide sequences derived from bovine NOGO. Grandpre et al, supra demonstrate that NOGO expression is predominantly associated with the CNS and not the peripheral nervous system (PNS). Cellular localization of NOGO protein appears to be predominantly reticluar in origin, however, NOGO is found on the surface of some oligodentrocytes. An active domain of NOGO has been identified, defined as residues 31-55 of a hydrophilic 66-residue lumenal/extracellular domain. A synthetic fragment corresponding to this sequence exhibits growth-cone collapsing and outgrowth inhibiting activities (Grandpre et al, supra).
A receptor for the NOGO-A extracellular domain (NOGO-66) is described in Fournier et al, 2001, Nature, 409, 341-346. Fournier et al, have shown that isolated NOGO-66 inhibits axonal extension but does not alter non-neuronal cell morphology. The receptor identified has a high affinity for soluble NOGO-66, and is expressed as a glycophosphatidylinostitol-linked protein on the surface of CNS neurons. Furthermore, the expression of the NOGO-66 receptor in neurons that are NOGO insensitive results in NOGO dependent inhibition of axonal growth in these cells. Cleavage ofthe NOGO-66 receptor and other glycophosphatidylinostitol-linked proteins from axonal surfaces renders neurons insensitive to NOGO-66 inhibition. As such, disruption ofthe interaction between NOGO-66 and the NOGO-66 receptor provides the possibility of treating a wide variety of neurological diseases, injuries, and conditions. Hauswirth and Flannery, International PCT Publication No. WO 98/48027, describe materials and methods for the specific expression of proteins in retinal photoreceptor cells consisting of an adeno-associated viral vector contacting a rod or cone-opsin promoter. In addition, ribozymes which degrade mutant mRNA are described for use in the treatment of retinitis pigmentosa.
Fechteler et al, Interanational PCT Publication No. WO 00/03004 describe ribozymes targeting presenilin-2 RNA for the use in treating neurodegenerative diseases such as Alzheimer's disease.
Eldadah et al, 2000, J. Neurosci., 20, 179-186, describe the protection of cerebellar granule cells from apoptosis induced by serum-potassium deprivation from ribozyme mediated inhibition of caspase-3.
Seidman et al, 1999, Antisense Nucleic Acid Drug Dev., 9, 333-340, describe in general terms, the use of antisense and ribozyme constructs for treatment of neurodegenerative diseases.
Denman et al, 1994, Nucleic Acids Research, 22, 2375-82, describe the ribozyme mediated degradation of beta-amyloid peptide precursor mRNA in COS-7 cells.
Schwab and Chen, International PCT publication No. WO 00/31235, describe NOGO proteins and inhibitors of NOGO.
Blatt et al, International PCT publication No. WO 01/59103, describe nucleic acid molecules for modulating expression of NOGO genes.
The following is a brief description of the physiological role of nuclear factor kappa B (NFKB), IKK kinases, and protein kinase PKR. Nuclear factor kappa B (NFKB) is a multiunit transcription factor which regulates the expression of genes involved in a number of physiologic and pathologic processes. NFKB is a key component of the TNF signaling pathway. These processes include, but are not limited to: apoptosis, immune, inflammatory and acute phase responses. The REL-A gene product (a.k.a. RelA or p65), and p50 subunits of NFKB, have been implicated in the induction of inflammatory responses and cellular transformation. NFKB exists in the cytoplasm as an inactive heterodimer of the p50 and p65 subunits. NFKB is complexed with an inhibitory protein complex, IkappaB (IKK complex), until activated by the appropriate stimuli. NFKB activation can occur following stimulation of a variety of cell types by inflammatory mediators, for example TNF and EL-1, and reactive oxygen intermediates. In response to induction, NFKB can stimulate production of pro- inflammatory cytokines such as TNF- alpha, IL-1 -beta, IL-6 and iNOS, thereby perpetuating a positive feedback loop. NFKB appears to play a role in a number of disease processes including: ischemia/reperfusion injury (CNS and myocardial), glomerulonephritis, sepsis, allergic airway inflammation, inflammatory bowel disease, infection, arthritis, and cancer.
The nuclear DNA-binding protein, NFKB, was first identified as a factor that binds and activates the immunoglobulin kappa light chain enhancer in B cells. NFKB now is known to activate transcription of a variety of other cellular genes (e.g., cytokines, adhesion proteins, oncogenes and viral proteins) in response to a variety of stimuli (e.g., phorbol esters, mitogens, cytokines and oxidative stress). In addition, molecular and biochemical characterization of NFKB has shown that the activity is due to a homodimer or heterodimer of a family of DNA binding subunits. Each subunit bears a stretch of 300 amino acids that is homologous to the oncogene, v-rel. The activity first described as NFKB is a heterodimer of p49 or p50 with p65. The p49 and p50 subunits of NFKB (encoded by the NF-kappa B2 or NF kappa BI genes, respectively) are generated from the precursors NFKBl (pi 05) or NFKB2 (pi 00). The p65 subunit of NFKB (now termed REL-A) is encoded by the rel- A locus.
The roles of each specific transcription-activating complex now are being elucidated in cells (Perkins, et al, 1992, Proc. Natl Acad. Sci USA, 89, 1529-1533). For instance, the heterodimer of NFKBl and Rel A (p50/p65) activates transcription of the promoter for the adhesion molecule, VCAM-1, while NFKB2/RelA heterodimers (p49/p65) actually inhibit transcription (Shu, et al, 1993, Mol. Cell. Biol, 13, 6283-6289). Conversely, heterodimers of NFKB2/RelA (p49/p65) act with Tat-I to activate transcription of the HIV genome, while NFKBl/RelA (p50/p65) heterodimers have little effect (Liu et al, 1992, J. Virol, 66, 3883- 3887). Similarly, blocking rel A gene expression with antisense oligonucleotides specifically blocks embryonic stem cell adhesion; blocking NFKBl gene expression with antisense oligonucleotides had no effect on cellular adhesion (Narayanan et al, 1993, Mol. Cell. Biol, 13, 3802-3810). Thus, the promiscuous role initially assigned to NFKB in transcriptional activation (Lenardo, and Baltimore, 1989, Cell, 58, 227-229) represents the sum of the activities of the rel family of DNA-binding proteins. This conclusion is supported by recent transgenic "knock-out" mice of individual members of the rel family. Such "knock-outs" show few developmental defects, suggesting that essential transcriptional activation functions can be performed by more than one member ofthe rel family. A number of specific inhibitors of NFKB function in cells exist, including treatment with phosphorothioate antisense oliogonucleotide, treatment with double-stranded NFKB binding sites, and over expression of the natural inhibitor MAD-3 (an Ikappa-B family member). These agents have been used to show that NFKB is required for induction of a number of molecules involved in cancer and or inflammation, as described below.
NFkB is required for phorbol ester-mediated induction of IL-6 (Kitajima, et al, 1992, Science, 258, 1792-5) and IL-8 (Kunsch and Rosen, 1993, Mol. Cell. Biol, 13, 6137-46).
NFkB is required for induction of the adhesion molecules ICAM-1 (Eck, et al, 1993, Mol. Cell. Biol, 13, 6530-6536), VCAM-1 (Shu et al, supra), and E-selectin (Read, et al, 1994, J. Exp. Med., 179, 503-512) on endothelial cells.
NFkB is involved in the induction of the integrin subunit, CD 18, and other adhesive properties of leukocytes (Eck et al, 1993 supra).
HER2/Neu overexpression induces NFKB via a PI3 -kinase/ Akt pathway involving calpain-mediated degradation of IKB-alpha. Breast cancer has been shown to typify the aberrant expression of NFKB/REL factors (Pianetti et al, 2001, Oncogene, 20, 1287-1299; Sovak et α/., 1999, J Clin. Invest., 100, 2952-2960).
Inhibition of NFKB activity has been shown to induce apoptosis in murine hepatocytes (Bellas et al, 1991, Am. J. Pathol, 151, 891-896).
NFKB has been shown to regulate cyclooxygenase-2 expression and cell proliferation in human gastric cancer cells (Joo Weon et al, 2001, Laboratory Investigation, 81, 349-360).
The above studies suggest that NFKB is integrally involved in the induction of cytokines and adhesion molecules by inflammatory mediators and is involved in the transformation of cancerous cells. Two reported studies point to another connection between NFKB and inflammation: glucocorticoids can exert their anti-inflammatory effects by inhibiting NFKB. The glucocorticoid receptor and p65 both act at NFKB binding sites in the ICAM-1 promoter (van de Stolpe, et al, 1994, J. Biol. Chem., 269, 6185-6192). Glucocorticoid receptor inhibits NFKB-mediated induction of IL-6 (Ray and Prefontaine, 1994 Proc. Natl Acad. Sci USA, 91, 752-756). Conversely, overexpression of p65 inhibits glucocorticoid induction of the mouse mammary tumor virus promoter. Finally, protein cross-linking and co-immunoprecipitation experiments demonstrated direct physical interaction between p65 and the glucocorticoid receptor.
The IKK complex that sequesters NFKB in the cytoplasm comprises D appaB (IκB) proteins (IκB-alpha, IκB-beta, IκB-epsilon, pl05, and plOO). The phosphorylation of IκB proteins results in the release of NFKB from the IκB complex which is transported to the nucleus via the unmasking of nuclear translocation signals. Phosphorylation marks IkB proteins for ubiquitination and degradation via the proteosome pathway. Most NFKB inducing stimuli initiate activation of an IKB kinase (IKK) complex that contains two catalytic subunits, IKK-alpha (IKKl) and IKK-beta (IKK2), that phosphorylate IκB-alpha and IκB- beta, with IKK-beta playing a predominant role in pro-inflammatory signaling. In addition to the two kinases, the IKK complex contains regulatory subunits, including IKK-gamma (NEMO/IKKAPl). IKK-gamma is a protein that is critical for the assembly of the IKK complex. IKK-gamma directly binds to IKK-beta and is required for activation of NFKB, for example by TNF-alpha, IL-1-beta, lipopolysaccharide, phorbol 12-myristate 13-acetate, the human T-cell lympho trophic virus (HTLV-1), or double stranded RNA. Genomic rearrangements in IKK-gamma have been shown to impair NFKB activation and result in incontinentia pigmenti. Additional proteins that associate with the IKK complex include, MEK kinase (MEKKl), NFKB inducing kinase (NIK), receptor interacting protein (RIP), protein kinase CK2, and IKK-associated protein (D AP), which appears to be associated with the IKB Kinase (IKK) complex, but does not appear to be an integral component of the tripartite IKK complex as does IKK-gamma (Krappmann et al, 2001, J. Biol. Chem., 275, 29779-87).
The RNA-dependent protein kinase PKR is a signal transducer for NFKB and IFN regulatory factor- 1. PKR is required for activation of NFKB by IFN-gamma via a STAT-1 independent pathway (Amitabha et al, 2001, J. Immunol, 166, 6170-6180). The induction of NFKB by PKR takes place though phosphorylation of IκB-alpha, and appears not to require the catalytic activity of PKR, thereby proceeding independently of the dsRNA-binding properties of PKR (Ishii et al, 2001, Oncogene, 20, 1900-1912). PKR also plays an important role in the regulation of protein synthesis by modulating the activity of eukaryotic initiation factor 2 (eIF-2-alpha) through interferon induction.
Kamiya, JP 2000253884, describes specific antisense oligonucleotides for inhibiting IκB-kinase subunit expression. Krappmann et al, 2001, J. Biol Chem., describe specific antisense oligonucleotides to IKK-gamma.
The following is a description of molecular targets involved in diseases or conditions related to allergic response. Asthma is a chronic inflammatory disorder of the lungs characterized by airflow obstruction, bronchial hyper-responsiveness, and airway inflammation. T-lymphocytes that produce TH2 cytokines and eosinophilic leukocytes infiltrate the airways. In the airway and in bronchial alveolar lavage (BAL) fluid of individuals with asthma, high concentrations of TH2 cytokines, interleukin-4 (E -4), H-5, and IL-13, are present along with increased levels of adenosine. In contrast to normal individuals, asthmatics respond to adenosine challenge with marked airway obstruction. Upon allergen challenge, mast cells are activated by cross-linked IgE-allergen complexes. Large amounts of prostaglandin D2 (PGD2), the major cyclooxygenase product of arachidonic acid are released. PGD2 is generated from PGH2 via the activity of prostaglandin D2 synthetase (PTGDS). PGD2 receptors and adenosine Al receptors are present in the lungs and airway along with various other tissues in response to allergic stimuli (Howarth, 1997, Allergy, 52, 12).
The significance of PGD2 as a mediator of allergic asthma has been established with the development of mice deficient in the PGD2 receptor (DP). DP is a heterotrimeric GTP- binding protein-coupled, rhodopsin-type receptor specific for PGD2 (Hirata et al, 1994, PNAS USA., 91, 11192). These mice fail to develop airway hyperreactivity and have greatly reduced eosinophil infiltration and cytokine accumulation in response to allergens. Upon allergen challenge mice deficient in the prostaglandin D2 (PGD2) receptor (DP) did not develop airway hyperactivity. Cytokine, lymphocyte and eosinophil accumulation in the lungs were greatly reduced (Matsuoka et al, 2000, Science, 287, 2013). The DP -/- mice exhibited no behavioral, anatomic, or histological abnormalities. Primary immune response is not affected by DP disruption.
Asthma affects more than 100 million people worldwide and more than 17 million Americans (5 % of the population). Since 1980 the incidence has more than doubled and deaths have tripled (5,000 deaths in 1995). Annual asthma-related healthcare costs in the US alone were estimated to exceed $14.5 billion in 2000. Current therapies such as inhalant anti- inflammatories and bronchodilators can be used to treat symptoms, however, these therapies do not prevent or cure asthma.
Sandberg et al, 2001, Prog. Respir. Res., 31, 370-373, describes ribozyme therapy for asthma and COPD.
Sullivan et al, International US 5,616,488, describes ribozymes targeting interleukin-5 for treatment and diagnosis of asthma and other inflammatory disorders.
Stinchcomb et al, International PCT Publication No. WO 95/23225, describes ribozymes and methods for inhibiting the expression of disease related genes including genes associated with asthma.
Nyce, International PCT Publication Nos. WO 00/62736, WO 00/09525, WO 99/13886, WO 98/23294, WO 96/40266 and US 6,025,339 describe specific antisense oligonucleotides targeting certain mRNAs encoding particular adenosine receptors.
Summary Of The Invention The invention features novel nucleic acid-based molecules, for example, enzymatic nucleic acid molecules, allozymes, antisense nucleic acids, 2-5A antisense chimeras, triplex forming oligonucleotides, decoy RNA, dsRNA, siRNA, aptamers, and antisense nucleic acids containing RNA cleaving chemical groups, and methods to modulate gene expression; for example, gene(s) encoding prostaglandin D2 receptor (PTGDR), prostaglandin D2 synthetase (PTGDS), and adenosine receptors (AR) such as adenosine receptor Al (ADORA1), A2a, A2b, and A3; gene(s) encoding NOGO-A, NOGO-B, NOGO-C, NI-35, NI-220, NI-250, myelin-associated glycoprotein, tenascin-R, NG-2 and/or their corresponding receptors; and genes encoding an IkappaB kinase (IKK) subunit or protein kinase PKR.
In one embodiment, the instant invention features nucleic-acid based techniques to inhibit the expression of NOGO-A (Accession No. AJ251383), NOGO-B (Accession No. AJ251384), and or NOGO-C (Accession No. AJ251385), NOGO-66 receptor (Accession No AF283463, Fournier et al, 2001, Nature, 409, 341-346), NI-35, NI-220, and/or NI-250, myelin-associated glycoprotein (Genbank Accession No M29273), tenascin-R (Genbank Accession No X98085), and NG-2 (Genbank Accession No X61945). The description below of the various aspects and embodiments is provided with reference to the exemplary NOGO- A and NOGO-66 receptor genes. However, the various aspects and embodiments are also directed to other genes which express NOGOA-like inhibitor proteins and other receptors involved in neurite outgrowth inhibition. Those additional genes can be analyzed for target sites using the methods described for NOGO and the NOGO-66 receptor, referred to alternatively as NOGO receptor. Thus, the inhibition and the effects of such inhibition ofthe other genes can be performed as described herein.
The invention features one or more enzymatic nucleic acid-based molecules and methods that independently or in combination modulate the expression of gene(s) encoding a member of the IKB kinase IKK complex or PKR. In particular embodiments, the invention features nucleic acid-based molecules and methods that modulate the expression of a member of the IKB kinase IKK complex, for example IKK-alpha (IKKl), IKK-beta (IKK2), or IKK- gamma (IKKγ) and/or a protein kinase PKR protein, such as IKK-alpha (IKKl) gene (Genbank Accession No. NM_001278); IKK-beta (IKK2) gene, for example (Genbank Accession No.AF080158), IKK-gamma (IKKγ) gene, for example (Genbank Accession No. NM_003639), and protein kinase PKR gene, for example (Genbank Accession No. NM_002759). The description below of the various aspects and embodiments is provided with reference to the exemplary IKK-gamma and PKR genes. IKK-gamma is also known as NEMO/ IKKAPl. However, the various aspects and embodiments are also directed to other genes which encode other subunits of the IKK complex, such as IKK-alpha (IKKl) or IKK- beta (IKK2). Those additional genes can be analyzed for target sites using the methods described for IKK-gamma or PKR. Thus, the inhibition and the effects of such inhibition of the other genes can be performed as described herein.
In one embodiment, an enzymatic nucleic acid molecule of the invention is in a hammerhead, Inozyme, Zinzyme, DNAzyme, Amberzyme, or G-cleaver configuration.
In another embodiment, a nucleic acid molecule of the invention comprises between 8 and 100 bases complementary to the RNA of the target gene. In another embodiment, a nucleic acid molecule of the invention comprises between 14 and 24 bases complementary to a RNA molecule ofthe target gene.
In one embodiment, an enzymatic nucleic acid molecule, antisense nucleic acid molecule, 2-5 A antisense chimera, triplex forming oligonucleotide, decoy RNA, dsRNA, siRNA, aptamer, or antisense nucleic acids containing RNA cleaving chemical groups of the invention is chemically synthesized.
In another embodiment, an enzymatic nucleic acid molecule, antisense nucleic acid molecule, 2-5A antisense chimera, triplex forming oligonucleotide, decoy RNA, dsRNA, siRNA, aptamer, or antisense nucleic acids containing RNA cleaving chemical groups of the invention comprises at least one 2'-sugar modification.
In another embodiment, an enzymatic nucleic acid molecule, antisense nucleic acid molecule, 2-5A antisense chimera, triplex forming oligonucleotide, decoy RNA, dsRNA, siRNA, aptamer, or antisense nucleic acids containing RNA cleaving chemical groups of the invention comprises at least one nucleic acid base modification.
In another embodiment, an enzymatic nucleic acid molecule, antisense nucleic acid molecule, 2-5A antisense chimera, triplex forming oligonucleotide, decoy RNA, dsRNA, siRNA, aptamer, or antisense nucleic acids containing RNA cleaving chemical groups of the invention comprises at least one phosphate backbone modification.
In one embodiment, the invention features a mammalian cell, for example a human cell, including the nucleic acid molecule ofthe invention.
In another embodiment, the invention features a method of reducing target gene expression or activity in a cell, comprising contacting the cell with a nucleic acid molecule of the invention, such as an enzymatic nucleic acid molecule, antisense nucleic acid molecule, 2-5A antisense chimera, triplex forming oligonucleotide, decoy RNA, dsRNA, siRNA, aptamer, or antisense nucleic acids containing RNA cleaving chemical groups, under conditions suitable for the reduction. In yet another embodiment, the invention features a method of treatment of a patient having a condition associated with the level of a target gene, such prostaglandin D2 receptor (PTGDR), prostaglandin D2 synthetase (PTGDS), adenosine receptors (AR) such as adenosine receptor Al (ADORA1), A2a, A2b, and A3, NOGO-A, NOGO-B, NOGO-C, NI- 35, NI-220, NI-250, myelin-associated glycoprotein, tenascin-R, NG-2 and/or their corresponding receptors, an DcappaB kinase (IKK) subunit and or protein kinase PKR, comprising contacting cells of the patient with an enzymatic nucleic acid molecule of the invention, under conditions suitable for the treatment.
In another embodiment, a method of treatment of a patient having a condition associated with the level of a target gene, such prostaglandin D2 receptor (PTGDR), prostaglandin D2 synthetase (PTGDS), adenosine receptors (AR) such as adenosine receptor Al (ADORA1), A2a, A2b, and A3, NOGO-A, NOGO-B, NOGO-C, NI-35, NI-220, NI-250, myelin-associated glycoprotein, tenascin-R, NG-2 and/or their corresponding receptors, an DcappaB kinase (IKK) subunit and/or protein kinase PKR is featured, wherein the method further comprises the use of one or more drug therapies under conditions suitable for the treatment.
In another embodiment, the invention features a method of cleaving a RNA molecule of a target gene, such prostaglandin D2 receptor (PTGDR), prostaglandin D2 synthetase (PTGDS), adenosine receptors (AR) such as adenosine receptor Al (ADORA1), A2a, A2b, and A3, NOGO-A, NOGO-B, NOGO-C, NI-35, NI-220, NI-250, myelin-associated glycoprotein, tenascin-R, NG-2 and/or their corresponding receptors, an DcappaB kinase (IKK) subunit and/or protein kinase PKR gene, comprising contacting an enzymatic nucleic acid molecule of the invention with a RNA molecule of the corresponding gene under conditions suitable for the cleavage, for example, wherein the cleavage is carried out in the presence of a divalent cation, such as Mg2+.
In one embodiment, a nucleic acid molecule of the invention comprises a cap structure, for example a 3',3'-linked or 5',5'-linked deoxyabasic ribose derivative, wherein the cap structure is at the 5'-end, or 3'-end, or both the 5'-end and the 3'-end ofthe enzymatic nucleic acid molecule.
In one embodiment, the invention features an expression vector comprising a nucleic acid sequence encoding at least one nucleic acid molecule of the invention, in a manner which allows expression ofthe nucleic acid molecule.
In another embodiment, the invention features a mammalian cell, for example, a human cell, including an expression vector ofthe invention. In yet another embodiment, the expression vector of the invention further comprises a sequence for an antisense nucleic acid molecule complementary to a RNA molecule of a target gene, such prostaglandin D2 receptor (PTGDR), prostaglandin D2 synthetase (PTGDS), adenosine receptors (AR) such as adenosine receptor Al (ADORA1), A2a, A2b, and A3, NOGO-A, NOGO-B, NOGO-C, NI-35, NI-220, NI-250, myelin-associated glycoprotein, tenascin-R, NG-2 and/or their corresponding receptors, an DcappaB kinase (IKK) subunit and or protein kinase PKR gene.
In one embodiment, an expression vector of the invention comprises a nucleic acid sequence encoding two or more nucleic acid molecules, such as enzymatic nucleic acid molecules, antisense, aptamers, decoys, siRNA, or 2-5 A chimeras which can be the same or different.
In one embodiment, the method of treatment features an enzymatic nucleic acid molecule of the invention comprises at least five ribose residues, at least ten 2'-O-methyl modifications, and a 3'- end modification, such as a 3 '-3' inverted abasic moiety. In another embodiment, an enzymatic nucleic acid molecule or antisense nucleic acid molecule of the invention further comprises phosphorothioate linkages on at least three of the 5' terminal nucleotides.
In another embodiment, the invention features a method of administering to a mammal, for example a human, an enzymatic nucleic acid molecule, antisense nucleic acid molecule, 2- 5 A antisense chimera, triplex forming oligonucleotide, decoy RNA, dsRNA, siRNA, aptamer, or antisense nucleic acid containing RNA cleaving chemical groups of the invention, comprising contacting the mammal with the nucleic acid molecule under conditions suitable for the administration, for example, in the presence of a delivery reagent such as a lipid, cationic lipid, phospholipid, or liposome.
In yet another embodiment, the invention features a method of administering to a mammal an enzymatic nucleic acid molecule, antisense nucleic acid molecule, 2-5A antisense chimera, triplex forming oligonucleotide, decoy RNA, dsRNA, siRNA, aptamer, or antisense nucleic acid containing RNA cleaving chemical groups ofthe indention in conjunction with a therapeutic agent, comprising contacting the mammal, for example a human, with the nucleic acid molecule and the therapeutic agent under conditions suitable for the administration.
In one embodiment, the invention features the use of an enzymatic nucleic acid molecule, which can be in a hammerhead, NCH, G-cleaver, Amberzyme, Zinzyme, and or
DNAzyme motif, to down-regulate the expression of a a target gene, such as prostaglandin
D2 receptor (PTGDR), prostaglandin D2 synthetase (PTGDS), adenosine receptors (AR) such as adenosine receptor Al (ADΟRA1), A2a, A2b, and A3, NOGO-A, NOGO-B, NOGO-C, NI-35, NI-220, NI-250, myelin-associated glycoprotein, tenascin-R, NG-2 and/or their corresponding receptors, an DcappaB kinase (JKK) subunit and/or protein kinase PKR gene.
By "inhibit", "down-regulate", or "reduce", it is meant that the expression of the gene, or level of RNA molecules or equivalent RNA molecules encoding one or more proteins or protein subunits, or activity of one or more proteins or protein subunits, such as prostaglandin D2 receptor (PTGDR), prostaglandin D2 synthetase (PTGDS), adenosine receptors (AR) such as adenosine receptor Al (ADORAl), A2a, A2b, and A3, NOGO-A, NOGO-B, NOGO-C, NI-35, NI-220, NI-250, myelin-associated glycoprotein, tenascin-R, NG-2 and/or their corresponding receptors, an DcappaB kinase (IKK) subunit and/or protein kinase PKR subunits, is reduced below that observed in the absence of the nucleic acid molecules of the invention. In one embodiment, inhibition, down-regulation or reduction with an enzymatic nucleic acid molecule is below that level observed in the presence of an enzymatically inactive or attenuated molecule that is able to bind to the same site on the target RNA molecule, but is unable to cleave that RNA molecule. In another embodiment, inhibition, down-regulation, or reduction with antisense oligonucleotides is below that level observed in the presence of, for example, an oligonucleotide with scrambled sequence or with mismatches. In another embodiment, inhibition, down-regulation, or reduction of the target gene with a nucleic acid molecule of the instant invention is greater in the presence of the nucleic acid molecule than in its absence.
By "up-regulate" is meant that the expression of a gene, or level of RNA molecules or equivalent RNA molecules encoding one or more proteins, protein subunits, or activity of one or more proteins or protein subunits, such as a target gene, such as prostaglandin D2 receptor (PTGDR), prostaglandin D2 synthetase (PTGDS), adenosine receptors (AR) such as adenosine receptor Al (ADORAl), A2a, A2b, and A3, NOGO-A, NOGO-B, NOGO-C, NI- 35, NI-220, NI-250, myelin-associated glycoprotein, tenascin-R, NG-2 and/or their corresponding receptors, an DcappaB kinase (IKK) subunit and/or protein kinase PKR subunits, is greater than that observed in the absence of the nucleic acid molecules of the invention. For example, the expression of a gene, such as prostaglandin D2 receptor (PTGDR), prostaglandin D2 synthetase (PTGDS), adenosine receptors (AR) such as adenosine receptor Al (ADORAl), A2a, A2b, and A3, NOGO-A, NOGO-B, NOGO-C, NI- 35, NI-220, NI-250, myelin-associated glycoprotein, tenascin-R, NG-2 and/or their corresponding receptors, an DcappaB kinase (IKK) subunit and or protein kinase PKR gene, can be increased in order to treat, prevent, ameliorate, or modulate a pathological condition caused or exacerbated by an absence or low level of gene expression.
By "modulate" is meant that the expression ofthe gene, or level of RNA molecules or equivalent RNA molecules encoding one or more protein subunits, or activity of one or more protein subunits is up-regulated or down-regulated, such that the expression, level, or activity is greater than or less than that observed in the absence of a nucleic acid molecule of the invention.
By "enzymatic nucleic acid molecule" it is meant a nucleic acid molecule that has complementarity in a substrate binding region to a specified gene target, and also has an enzymatic activity that is active to specifically cleave target a RNA molecule. That is, the enzymatic nucleic acid molecule is able to intermolecularly cleave a RNA molecule and thereby inactivate a target RNA molecule. These complementary regions allow sufficient hybridization of an enzymatic nucleic acid molecule to a target RNA molecule and thus permit cleavage. One hundred percent complementarity is preferred, but complementarity as low as 50-75% can also be useful in this invention (see for example Werner and Uhlenbeck, 1995, Nucleic Acids Research, 23, 2092-2096; Hammann et al, 1999, Antisense and Nucleic Acid Drug Dev., 9, 25-31). The nucleic acids can be modified at the base, sugar, and/or phosphate groups. The term enzymatic nucleic acid is used interchangeably with phrases such as ribozymes, catalytic RNA, enzymatic RNA, catalytic DNA, aptazyme or aptamer-binding ribozyme, regulatable ribozyme, catalytic oligonucleotides, nucleozyme, DNAzyme, RNA enzyme, endoribonuclease, endonuclease, minizyme, leadzyme, oligozyme or DNA enzyme. All of these terminologies describe nucleic acid molecules with enzymatic activity. The specific enzymatic nucleic acid molecules described in the instant application are not limiting in the invention and those skilled in the art will recognize that all that is important in an enzymatic nucleic acid molecule of this invention is that it has a specific substrate binding site that is complementary to one or more of the target nucleic acid regions, and that it have nucleotide sequences within or surrounding that substrate binding site which impart a nucleic acid cleaving and/or ligation activity to the molecule (Cech et al, U.S. Patent No. 4,987,071; Cech et al, 1988, 260 JAMA 3030).
By "nucleic acid molecule" as used herein is meant a molecule having nucleotides. The nucleic acid can be single, double, or multiple stranded and can comprise modified or unmodified nucleotides or non-nucleotides or various mixtures and combinations thereof. Exemplary nucleic acid molecules of the invention include enzymatic nucleic acid molecules, allozymes, antisense nucleic acids, 2-5A antisense chimeras, triplex forming oligonucleotides, decoy RNA, dsRNA, siRNA, aptamers, and/or antisense nucleic acids containing RNA cleaving chemical groups.
By "enzymatic portion" or "catalytic domain" is meant that portion region of the enzymatic nucleic acid molecule essential for cleavage of a nucleic acid substrate (for example see Figures 1-4).
By "substrate binding arm" or "substrate binding domain" is meant that portion/region of a enzymatic nucleic acid that is able to interact, for example via complementarity {i.e., able to base-pair with), with a portion of its substrate. Such complementarity can be 100%, but can be less if desired. For example, as few as 10 bases out of 14 can be base-paired (see for example Werner and Uhlenbeck, 1995, Nucleic Acids Research, 23, 2092-2096; Hammann et al, 1999, Antisense and Nucleic Acid Drug Dev., 9, 25-31). Examples of such arms are shown generally in Figures 1-4. That is, these arms contain sequences within an enzymatic nucleic acid that are intended to bring enzymatic nucleic acid and target RNA together through complementary base-pairing interactions. The enzymatic nucleic acid of the invention can have binding arms that are contiguous or non-contiguous and can be of varying lengths. The length ofthe binding arm(s) can be greater than or equal to four nucleotides and of sufficient length to stably interact with a target RNA; in one embodiment they can be 12- 100 nucleotides; in another embodiment they can be 14-24 nucleotides long (see for example Werner and Uhlenbeck, supra; Hamman et al, supra; Hampel et al, EP0360257; Berzal- Herranze et al, 1993, EMBO J., 12, 2567-73) or between 8 and 14 nucleotides long. If two binding arms are chosen, the design is such that the length of the binding arms are symmetrical {i.e., each of the binding arms is of the same length; e.g., four and four, five and five nucleotides, or six and six nucleotides, or seven and seven nucleotides long) or asymmetrical {i.e., the binding arms are of different length; e.g., three and five, six and three nucleotides; three and six nucleotides long; four and five nucleotides long; four and six nucleotides long; four and seven nucleotides long; and the like).
By "Inozyme" or "NCH" motif or configuration is meant, an enzymatic nucleic acid molecule comprising a motif as is generally described as NCH Rz in Figure 1. Inozymes possess endonuclease activity to cleave RNA substrates having a cleavage triplet NCH/, where N is a nucleotide, C is cytidine and H is adenosine, uridine or cytidine, and / represents the cleavage site. H is used interchangeably with X. Inozymes can also possess endonuclease activity to cleave RNA substrates having a cleavage triplet NCN/, where N is a nucleotide, C is cytidine, and / represents the cleavage site. "I" in Figure 1 represents an Inosine nucleotide, including a ribo-Inosine or xylo-Inosine nucleoside.
By "G-cleaver" motif or configuration is meant, an enzymatic nucleic acid molecule comprising a motif as is generally described as G-cleaver Rz in Figure 1. G-cleavers possess endonuclease activity to cleave RNA substrates having a cleavage triplet NYN/, where N is a nucleotide, Y is uridine or cytidine and / represents the cleavage site. G-cleavers can be chemically modified as is generally shown in Figure 1.
By "amberzyme" motif or configuration is meant, an enzymatic nucleic acid molecule comprising a motif as is generally described in Figure 2. Amberzymes possess endonuclease activity to cleave RNA substrates having a cleavage triplet NG/N, where N is a nucleotide, G is guanosine, and / represents the cleavage site. Amberzymes can be chemically modified to increase nuc lease stability through substitutions as are generally shown in Figure 2. In addition, differing nucleoside and/or non-nucleoside linkers can be used to substitute the 5'- gaaa-3' loops shown in the figure. Amberzymes represent a non-limiting example of an enzymatic nucleic acid molecule that does not require a ribonucleotide (2' -OH) group within its own nucleic acid sequence for activity.
By "zinzyme" motif or configuration is meant, an enzymatic nucleic acid molecule comprising a motif as is generally described in Figure 3. Zinzymes possess endonuclease activity to cleave RNA substrates having a cleavage triplet including but not limited to YG/Y, where Y is uridine or cytidine, and G is guanosine and / represents the cleavage site. Zinzymes can be chemically modified to increase nuclease stability through substitutions as are generally shown in Figure 3, including substituting 2'-O-methyl guanosine nucleotides for guanosine nucleotides. In addition, differing nucleotide and/or non-nucleotide linkers can be used to substitute the 5'-gaaa-2' loop shown in the figure. Zinzymes represent a non- limiting example of an enzymatic nucleic acid molecule that does not require a ribonucleotide (2' -OH) group within its own nucleic acid sequence for activity.
By 'DNAzyme' is meant, an enzymatic nucleic acid molecule that does not require the presence of a 2' -OH group within its own nucleic acid sequence for activity. In particular embodiments the enzymatic nucleic acid molecule can have an attached linker or linkers or other attached or associated groups, moieties, or chains containing one or more nucleotides with 2'-OH groups. DNAzymes can be synthesized chemically or expressed endogenously in vivo, by means of a single stranded DNA vector or equivalent thereof. An example of a DNAzyme is shown in Figure 4 and is generally reviewed in Usman et al, US patent No., 6,159,714; Chartrand et al, 1995, NAR 23, 4092; Breaker et al, 1995, Chem. Bio. 2, 655; Santoro et al, 1997, PNAS 94, 4262; Breaker, 1999, Nature Biotechnology, 17, 422-423; and Santoro et. al, 2000, J. Am. Chem. Soc, 122, 2433-39. The "10-23" DNAzyme motif is one particular type of DNAzyme that was evolved using in vitro selection (see Santoro et al, supra). Additional DNAzyme motifs can be selected for using techniques similar to those described in these references, and hence, are within the scope ofthe present invention.
By "sufficient length" is meant an oligonucleotide of greater than or equal to 3 nucleotides that is of a length great enough to provide the intended function under the expected condition. For example, for binding arms of enzymatic nucleic acid "sufficient length" means that the binding arm sequence is long enough to provide stable binding to a target site under the expected binding conditions. The binding arms are not so long as to prevent useful turnover ofthe nucleic acid molecule.
By "stably interact" is meant interaction of the oligonucleotides with target nucleic acid {e.g., by forming hydrogen bonds with complementary nucleotides in the target under physiological conditions) that is sufficient to the intended purpose (e.g., cleavage of target RNA by an enzyme).
By "equivalent" or "related" RNA to NOGO is meant to include those naturally occurring RNA molecules having homology (partial or complete) to NOGO-A, NOGO-B, NOGO-C and/or NOGO receptor proteins or encoding for proteins with similar function as NOGO or NOGO receptor proteins in various organisms, including human, rodent, primate, rabbit, pig, protozoans, fungi, plants, and other microorganisms and parasites. The equivalent RNA sequence also includes in addition to the coding region, regions such as 5 '-untranslated region, 3 '-untranslated region, introns, intron-exon junction and the like.
By "equivalent" or "related" RNA to IKK-gamma is meant to include those naturally occurring RNA molecules having homology (partial or complete) to IKK-gamma proteins or encoding for proteins with similar function as IKK-gamma proteins in various organisms, including human, rodent, primate, rabbit, pig, protozoans, fungi, plants, and other microorganisms and parasites. The equivalent RNA sequence also includes in addition to the coding region, regions such as 5 '-untranslated region, 3 '-untranslated region, introns, intron- exon junction and the like.
By "equivalent" or "related" RNA to PKR is meant to include those naturally occurring RNA molecules having homology (partial or complete) to PKR proteins or encoding for proteins with similar function as PKR proteins in various organisms, including human, rodent, primate, rabbit, pig, protozoans, fungi, plants, and other microorganisms and parasites. The equivalent RNA sequence also includes in addition to the coding region, regions such as 5 '-untranslated region, 3 '-untranslated region, introns, intron-exon junction and the like.
By "equivalent" or "related" RNA to PTGDS is meant to include RNA molecules having homology (partial or complete) to RNA molecules encoding PTGDS proteins or encoding proteins with similar function as PTGDS proteins in various organisms, including human, rodent, primate, rabbit, pig, plants, protozoans, fungi, and other microorganisms and parasites. The equivalent RNA sequence can also include in addition to the coding region, regions such as 5 '-untranslated region, 3 '-untranslated region, introns, intron-exon junction and the like.
By "equivalent" or "related" RNA to PTGDR is meant to include RNA molecules having homology (partial or complete) to RNA molecules encoding PTGDR proteins or encoding proteins with similar function as PTGDR proteins in various organisms, including human, rodent, primate, rabbit, pig, plants, protozoans, fungi, and other microorganisms and parasites. The equivalent RNA sequence can also include in addition to the coding region, regions such as 5 '-untranslated region, 3 '-untranslated region, introns, intron-exon junction and the like.
By "equivalent" or "related" RNA to ADORAl is meant to include RNA molecules having homology (partial or complete) to RNA molecule encoding ADORAl proteins or encoding proteins with similar function as ADORAl proteins in various organisms, including human, rodent, primate, rabbit, pig, plants, protozoans, fungi, and other microorganisms and parasites. The equivalent RNA sequence can also include in addition to the coding region, regions such as 5 '-untranslated region, 3 '-untranslated region, introns, intron-exon junction and the like.
By "homology" is meant the nucleotide sequence of two or more nucleic acid molecules is partially or completely identical.
By "antisense nucleic acid", it is meant a non-enzymatic nucleic acid molecule that binds to target RNA by means of RNA-RNA or RNA-DNA or RNA-PNA (protein nucleic acid; Egholm et al, 1993 Nature 365, 566) interactions and alters the activity of the target RNA (for a review, see Stein and Cheng, 1993 Science 261, 1004 and Woolf et al, US patent No. 5,849,902). Typically, antisense molecules are complementary to a target sequence along a single contiguous sequence of the antisense molecule. However, in certain embodiments, an antisense molecule can bind to substrate such that the substrate molecule forms a loop, and/or an antisense molecule can bind such that the antisense molecule forms a loop. Thus, the antisense molecule can be complementary to two (or even more) non-contiguous substrate sequences or two (or even more) non-contiguous sequence portions of an antisense molecule can be complementary to a target sequence or both. For a review of current antisense strategies, see Schmajuk et al, 1999, J. Biol. Chem., 21 A, 21783-21789, Delihas et al, 1997, Nature, 15, 751-753, Stein et al, 1997, Antisense N. A. Drug Dev., 7, 151, Crooke, 2000, Methods Enzymol, 313, 3-45; Crooke, 1998, Biotech. Genet. Eng. Rev., 15, 121-157, Crooke, 1997, Ad. Pharmacol, 40, 1-49. In addition, antisense DNA can be used to target RNA by means of DNA-RNA interactions, thereby activating RNase H, which digests the target RNA in the duplex. The antisense oligonucleotides can comprise one or more RNAse H activating region, which is capable of activating RNAse H cleavage of a target RNA. Antisense DNA can be synthesized chemically or expressed via the use of a single stranded DNA expression vector or equivalent thereof.
By "RNase H activating region" is meant a region (generally greater than or equal to 4-
25 nucleotides in length, and in one embodiment from 5-11 nucleotides in length) of a nucleic acid molecule capable of binding to a target RNA to form a non-covalent complex that is recognized by cellular RNase H enzyme (see for example Arrow et al, US 5,849,902; Arrow et al, US 5,989,912). The RNase H enzyme binds to the nucleic acid molecule-target RNA complex and cleaves the target RNA sequence. The RNase H activating region comprises, for example, phosphodiester, phosphorothioate (at least four of the nucleotides are phosphorothiote substitutions; and in another embodiment, 4-11 of the nucleotides are phosphorothiote substitutions); phosphorodithioate, 5'-thiophosphate, or methylphosphonate backbone chemistry or a combination thereof. In addition to one or more backbone chemistries described above, the RNase H activating region can also comprise a variety of sugar chemistries. For example, the RNase H activating region can comprise deoxyribose, arabino, fluoroarabino or a combination thereof, nucleotide sugar chemistry. Those skilled in the art will recognize that the foregoing are non-limiting examples and that any combination of phosphate, sugar and base chemistry of a nucleic acid that supports the activity of RNase H enzyme is within the scope of the definition of the RNase H activating region and the instant invention.
By "2-5 A antisense chimera" is meant an antisense oligonucleotide containing a 5'- phosphorylated 2'-5'-linked adenylate residue. These chimeras bind to target RNA in a sequence-specific manner and activate a cellular 2-5 A-dependent ribonuclease which, in turn, cleaves the target RNA (Torrence et al, 1993 Proc. Natl. Acad. Sci. USA 90, 1300; Silverman et al, 2000, Methods Enzymol, 313, 522-533; Player and Torrence, 1998, Pharmacol. Ther., 78, 55-113).
By "aptamer" or "nucleic acid aptamer" as used herein is meant a nucleic acid molecule that binds specifically to a target molecule wherein the nucleic acid molecule has sequence that is distinct from sequence recognized by the target molecule in its natural setting.
Alternately, an aptamer can be a nucleic acid molecule that binds to a target molecule where the target molecule does not naturally bind to a nucleic acid. The target molecule can be any molecule of interest. For example, the aptamer can be used to bind to a ligand-binding domain of a protein, thereby preventing interaction of the naturally occurring ligand with the protein. This is a non-limiting example and those in the art will recognize that other embodiments can be readily generated using techniques generally known in the art, see for example Gold et al, 1995, Annu. Rev. Biochem., 64, 763; Brody and Gold, 2000, J.
Biotechnol, 74, 5; Sun, 2000, Curr. Opin. Mol. Ther., 2, 100; Kusser, 2000, J Biotechnol, 74, 27; Hermann and Patel, 2000, Science, 287, 820; and Jayasena, 1999, Clinical Chemistry,
45, 1628.
By "triplex forming oligonucleotides" is meant an oligonucleotide that can bind to a double-stranded DNA in a sequence-specific manner to form a triple-strand helix. Formation of such triple helix structure has been shown to inhibit transcription of the targeted gene (Duval- Valentin et al, 1992 Proc. Natl. Acad. Sci. USA 89, 504; Fox, 2000, Curr. Med.
Chem., 1, 17-37; Praseuth et al, 2000, Biochim. Biophys. Acta, 1489, 181-206). By "gene" it is meant a nucleic acid that encodes an RNA, for example, nucleic acid sequences including but not limited to structural genes encoding a polypeptide.
"Complementarity" refers to the ability of a nucleic acid to form hydrogen bond(s) with another RNA molecule by either traditional Watson-Crick or other non-traditional types. In reference to the nucleic molecules of the present invention, the binding free energy for a nucleic acid molecule with its target or complementary sequence is sufficient to allow the relevant function of the nucleic acid to proceed, e.g., enzymatic nucleic acid cleavage, antisense or triple helix inhibition. Determination of binding free energies for nucleic acid molecules is well known in the art (see, e.g., Turner et al, 1987, CSH Symp. Quant. Biol. LH pp.123-133; Frier et al, 1986, Proc. Nat. Acad. Sci. USA 83:9373-9377; Turner et al, 1987, J. Am. Chem. Soc. 109:3783-3785). A percent complementarity indicates the percentage of contiguous residues in a nucleic acid molecule that can form hydrogen bonds (e.g., Watson- Crick base pairing) with a second nucleic acid sequence (e.g., 5, 6, 7, 8, 9, 10 out of 10 being 50%, 60%, 70%, 80%), 90%), and 100% complementary). "Perfectly complementary" means that all the contiguous residues of a nucleic acid sequence will hydrogen bond with the same number of contiguous residues in a second nucleic acid sequence.
By "RNA" is meant a molecule comprising at least one ribonucleotide residue. By "ribonucleotide" or "2'-OH" is meant a nucleotide with a hydroxyl group at the 2' position of a β-D-ribo-furanose moiety.
By "decoy RNA" is meant an RNA molecule or aptamer that is designed to preferentially bind to a predetermined ligand. Such binding can result in the inhibition or activation of a target molecule. The decoy RNA or aptamer can compete with a naturally occurring binding target for the binding of a specific ligand. For example, it has been shown that over-expression of HIV trans-activation response (TAR) RNA can act as a "decoy" and efficiently binds HIV tat protein, thereby preventing it from binding to TAR sequences encoded in the HIV RNA (Sullenger et al, 1990, Cell, 63, 601-608). This is but a specific example and those in the art will recognize that other embodiments can be readily generated using techniques generally known in the art, see for example Gold et al, 1995, Annu. Rev. Biochem., 64, 763; Brody and Gold, 2000, J Biotechnol, 74, 5; Sun, 2000, Curr. Opin. Mol. Ther., 2, 100; Kusser, 2000, J. Biotechnol, 14, 27; Hermann and Patel, 2000, Science, 287, 820; and Jayasena, 1999, Clinical Chemistry, 45, 1628. Similarly, a decoy RNA can be designed to bind to a D2 receptor and block the binding of PTGDS or a decoy RNA can be designed to bind to PTGDS and prevent interaction with the D2 receptor.
The term "short interfering RNA" or "siRNA" as used herein refers to a double stranded nucleic acid molecule capable of RNA interference "RNAi", see for example Bass,
2001, Nature, 411, 428-429; Elbashir et al, 2001, Nature, 411, 494-498; and Kreutzer et al, International PCT Publication No. WO 00/44895; Zernicka-Goetz et al, International PCT Publication No. WO 01/36646; Fire, International PCT Publication No. WO 99/32619; Plaetinck et al, International PCT Publication No. WO 00/01846; Mello and Fire, International PCT Publication No. WO 01/29058; Deschamps-Depaillette, International PCT Publication No. WO 99/07409; and Li et al, International PCT Publication No. WO 00/44914. As used herein, siRNA molecules need not be limited to those molecules containing only RNA, but further encompasses chemically modified nucleotides and non- nucleo tides.
The term "allozyme" as used herein refers to an allosteric enzymatic nucleic acid molecule, see, e.g., George et al, US Patent Nos. 5,834,186 and 5,741,679, Shih et al, US Patent No. 5,589,332, Nathan et al, US Patent No 5,871,914, Nathan and Ellington, International PCT publication No. WO 00/24931, Breaker et al, International PCT Publication Nos. WO 00/26226 and 98/27104, and Sullenger et al, International PCT publication No. WO 99/29842. The term "2-5A chimera" as used herein refers to an oligonucleotide containing a 5'-phosphorylated 2'-5'-linked adenylate residue. These chimeras bind to target RNA in a sequence-specific manner and activate a cellular 2-5A- dependent ribonuclease which, in turn, cleaves the target RNA (Torrence et al, 1993 Proc. Natl. Acad. Sci. USA 90, 1300; Silverman et al, 2000, Methods Enzymol, 313, 522-533; Player and Torrence, 1998, Pharmacol. Ther., 78, 55-113).
The term "triplex forming oligonucleotides" as used herein refers to an oligonucleotide that can bind to a double-stranded DNA in a sequence-specific manner to form a triple-strand helix. Formation of such triple helix structure has been shown to inhibit transcription of the targeted gene (Duval-Valentin et al, 1992 Proc. Natl. Acad. Sci. USA 89, 504; Fox, 2000, Curr. Med. Chem., 1, 17-37; Praseuth et. al, 2000, Biochim. Biophys. Acta, 1489, 181-206). Several varieties of naturally-occurring enzymatic RNAs are known presently. Each can catalyze the hydrolysis of RNA phosphodiester bonds in trans (and thus can cleave other RNA molecules) under physiological conditions. Table I summarizes some of the characteristics of these ribozymes. In general, enzymatic nucleic acids act by first binding to a target RNA. Such binding occurs through the target binding portion of a enzymatic nucleic acid that is held in close proximity to an enzymatic portion ofthe molecule that acts to cleave the target RNA. Thus, the enzymatic nucleic acid first recognizes and then binds a target RNA through complementary base-pairing, and once bound to the correct site, acts enzymatically to cut the target RNA. Strategic cleavage of such a target RNA will destroy its ability to direct synthesis of an encoded protein. After an enzymatic nucleic acid has bound and cleaved its RNA target, it is released from that RNA to search for another target and can repeatedly bind and cleave new targets. Thus, a single ribozyme molecule is able to cleave many molecules of target RNA. In addition, the ribozyme is a highly specific inhibitor of gene expression, with the specificity of inhibition depending not only on the base-pairing mechanism of binding to the target RNA, but also on the mechanism of target RNA cleavage. Single mismatches, or base-substitutions, near the site of cleavage can completely eliminate catalytic activity of a ribozyme.
In one embodiment of the inventions described herein, the enzymatic nucleic acid molecule is formed in a hammerhead or hairpin motif, but can also be formed in the motif of a hepatitis delta virus, group I intron, group π intron or RNase P RNA (in association with an RNA guide sequence), Neurospora VS RNA, DNAzymes, NCH cleaving motifs, or G- cleavers. Examples of such hammerhead motifs are described by Dreyfus, supra, Rossi et al, 1992, AIDS Research and Human Retroviruses 8, 183; of hairpin motifs by Hampel et al, EP0360257, Hampel and Tritz, 1989 Biochemistry 28, 4929, Feldstein et al, 1989, Gene 82, 53, Haseloff and Gerlach, 1989, Gene, 82, 43, and Hampel et al, 1990 Nucleic Acids Res. 18, 299; Chowrira & McSwiggen, US. Patent No. 5,631,359; of the hepatitis delta vims motif is described by Perrotta and Been, 1992 Biochemistry 31, 16; of the RNase P motif by Guerrier- Takada et al, 1983 Cell 35, 849; Forster and Altaian, 1990, Science 249, 783; Li and Altaian, 1996, Nucleic Acids Res. 24, 835; Neurospora VS RNA ribozyme motif is described by Collins (Saville and Collins, 1990 Cell 61, 685-696; Saville and Collins, 1991 Proc. Natl. Acad. Sci. USA 88, 8826-8830; Collins and Olive, 1993 Biochemistry 32, 2795-2799; Guo and Collins, 1995, EMBO. J. 14, 363); Group fl introns are described by Griffin et al, 1995, Chem. Biol. 2, 761; Michels and Pyle, 1995, Biochemistry 34, 2965; Pyle et al, International PCT Publication No. WO 96/22689; of the Group I intron by Cech et al, U.S. Patent 4,987,071 and of DNAzymes by Usman et al, International PCT Publication No. WO 95/11304; Chartrand et al, 1995, NAR 23, 4092; Breaker et al, 1995, Chem. Bio. 2, 655; Santoro et al, 1997, PNAS 94, 4262, and Beigelman et al, International PCT publication No. WO 99/55857. NCH cleaving motifs are described in Ludwig & Sproat, International PCT Publication No. WO 98/58058; and G-cleavers are described in Kore et al, 1998, Nucleic Acids Research 26, 4116-4120 and Eckstein et al, International PCT Publication No. WO 99/16871. Additional motifs such as the Aptazyme (Breaker et al, WO 98/43993), Amberzyme (Class I motif; Figure 2; Beigelman et al, U.S. Serial No. 09/301,511) and Zinzyme (Figure 3) (Beigelman et al, U.S. Serial No. 09/301,511), all included by reference herein including drawings, can also be used in the present invention. These specific motifs or configurations are not limiting in the invention and those skilled in the art will recognize that all that is important in an enzymatic nucleic acid molecule of this invention is that it has a specific substrate binding site which is complementary to one or more ofthe target gene RNA regions, and that it have nucleotide sequences within or surrounding that substrate binding site which impart an RNA cleaving activity to the molecule (Cech et al, U.S. Patent No. 4,987,071). In one embodiment of the present invention, a nucleic acid molecule of the instant invention can be between 12 and 100 nucleotides in length. Exemplary enzymatic nucleic acid molecules of the invention are shown in Tables III-XXIII. For example, enzymatic nucleic acid molecules of the invention can be between 15 and 50 nucleotides in length, and in another embodiment between 25 and 40 nucleotides in length, e.g., 34, 36, or 38 nucleotides in length (for example see Jarvis et al, 1996, J. Biol. Chem., 271, 29107-29112). Exemplary DNAzymes ofthe invention are can between 15 and 40 nucleotides in length, and in one embodiment, between 25 and 35 nucleotides in length, e.g., 29, 30, 31, or 32 nucleotides in length (see, e.g., Santoro et al, 1998, Biochemistry, 37, 13330-13342; Chartrand et al, 1995, Nucleic Acids Research, 23, 4092-4096). Exemplary antisense molecules of the invention can be between 15 and 75 nucleotides in length, and in one embodiment between 20 and 35 nucleotides in length, e.g., 25, 26, 27, or 28 nucleotides in length (see for example Woolf et al, 1992, PNAS, 89, 7305-7309; Milner et al, 1997, Nature Biotechnology, 15, 537-541). Exemplary triplex forming oligonucleotide molecules of the invention are between 10 and 40 nucleotides in length, and in one embodiment are between 12 and 25 nucleotides in length, e.g., 18, 19, 20, or 21 nucleotides in length (see for example Maher et al, 1990, Biochemistry, 29, 8820-8826; Strobel and Dervan, 1990, Science, 249, 73-75). Those skilled in the art will recognize that all that is required is for the nucleic acid molecule to be of length and conformation sufficient and suitable for the nucleic acid molecule to catalyze a reaction contemplated herein. The length of the nucleic acid molecules ofthe instant invention are not limiting within the general limits stated.
In one embodiment, a nucleic acid molecule that modulates, for example, down- regulates, the expression of a target gene comprises between 8 and 100 bases complementary to a RNA molecule of prostaglandin D2 receptor (PTGDR), prostaglandin D2 synthetase (PTGDS), adenosine receptors (AR) such as adenosine receptor Al (ADORAl), A2a, A2b, and A3, NOGO-A, NOGO-B, NOGO-C, NI-35, NI-220, NI-250, myelin-associated glycoprotein, tenascin-R, NG-2 and/or their corresponding receptors, an DcappaB kinase (IKK) subunit and/or protein kinase PKR. In another embodiment, a nucleic acid molecule that modulates the expression of a target gene comprises between 14 and 24 bases complementary to a RNA molecule of prostaglandin D2 receptor (PTGDR), prostaglandin D2 synthetase (PTGDS), adenosine receptors (AR) such as adenosine receptor Al (ADORAl), A2a, A2b, and A3, NOGO-A, NOGO-B, NOGO-C, NI-35, NI-220, NI-250, myelin- associated glycoprotein, tenascin-R, NG-2 and/or their corresponding receptors, an DcappaB kinase (IKK) subunit and or protein kinase PKR.
The invention provides a method for producing a class of nucleic acid-based gene modulating agents that exhibit a high degree of specificity for the RNA of a desired target. For example, the enzymatic nucleic acid molecule is can be targeted to a highly conserved sequence region of target RNAs encoding prostaglandin D2 receptor (PTGDR), prostaglandin D2 synthetase (PTGDS), adenosine receptors (AR) such as adenosine receptor Al (ADORAl), A2a, A2b, and A3, NOGO-A, NOGO-B, NOGO-C, NI-35, NI-220, NI-250, myelin-associated glycoprotein, tenascin-R, NG-2 and or their corresponding receptors, an DcappaB kinase (IKK) subunit and/or protein kinase PKR (e.g., prostaglandin D2 receptor (PTGDR)), prostaglandin D2 synthetase (PTGDS), adenosine receptors (AR) such as adenosine receptor Al (ADORAl), A2a, A2b, and A3, NOGO-A, NOGO-B, NOGO-C, NI- 35, NI-220, NI-250, myelin-associated glycoprotein, tenascin-R, NG-2 and/or their corresponding receptors, an DcappaB kinase (IKK) subunit and/or protein kinase PKR genes) such that specific treatment of a disease or condition can be provided with either one or several nucleic acid molecules ofthe invention. Such nucleic acid molecules can be delivered exogenously to specific tissue or cellular targets as required. Alternatively, the nucleic acid molecules {e.g., ribozymes, antisense, aptamers, and/or siRNA) can be expressed from DNA and/or RNA vectors that are delivered to specific cells.
As used in herein "cell" is used in its usual biological sense, and does not refer to an entire multicellular organism. The cell can, for example, be in vitro, e.g., in cell culture, or present in a multicellular organism, including,, e.g., birds, plants and mammals such as humans, cows, sheep, apes, monkeys, swine, dogs, and cats. The cell may be prokaryotic (e.g., bacterial cell) or eukaryotic (e.g., mammalian or plant cell).
By "NOGO proteins" is meant, a protein, protein receptor or a mutant protein derivative thereof, comprising neuronal inhibitor activity, preferably CNS neuronal growth inhibitor activity.
By "IKK-gamma proteins" is meant, a peptide or protein comprising a IKK-gamma or NEMO/ IKKAPl component of the IKK complex, for example a regulatory IKK subunit involved in the assembly of the high molecular weight IKK complex and/or induction of NFKB.
By "PKR proteins" is meant, a peptide or protein comprising a protein kinase PKR activity, for example the activation of NFKB.
By "PTGDR proteins" is meant, a protein receptor or a mutant protein or peptide derivative thereof, having prostaglandin D2 receptor activity, for example, having the ability to bind prostaglandin D2 and/or having GTP -binding protein coupled activity.
By "PTGDS proteins" is meant, a prostaglandin synthetase protein or a mutant protein or peptide derivative thereof, having prostaglandin D2 synthetase activity, for example, having the ability to convert PGH2 to PGD2. By "highly conserved sequence region" is meant, a nucleotide sequence of one or more regions in a target gene does not vary significantly from one generation to the other or from one biological system to the other.
The nucleic acid-based inhibitors of the invention can be added directly, or can be complexed with cationic lipids, packaged within liposomes, or otherwise delivered to target cells or tissues, for example by pulmonary delivery of an aerosol formulation with an inhaler or nebulizer. The nucleic acid or nucleic acid complexes can be locally administered to relevant tissues ex vivo, or in vivo through inhalation, injection or infusion pump, with or without their incorporation in biopolymers. In preferred embodiments, the enzymatic nucleic acid inhibitors comprise sequences that are complementary to the substrate sequences in Tables III to XXIII. Examples of such enzymatic nucleic acid molecules also are shown in Tables III to XXIII. Examples of such enzymatic nucleic acid molecules consist essentially of sequences defined in these tables.
In another embodiment, the invention features antisense nucleic acid molecules, siRNA and 2-5 A chimeras including sequences complementary to the substrate sequences shown in
Tables III to XXIII. Such nucleic acid molecules can include sequences as shown for the binding arms of the enzymatic nucleic acid molecules in Tables III to XXIII. Similarly, triplex molecules can be provided targeted to the corresponding DNA target regions, and containing the DNA equivalent of a target sequence or a sequence complementary to the specified target (substrate) sequence. Typically, antisense molecules are complementary to a target sequence along a single contiguous sequence of the antisense molecule. However, in certain embodiments, an antisense molecule can bind to substrate such that the substrate molecule forms a loop, and/or an antisense molecule can bind such that the antisense molecule forms a loop. Thus, the antisense molecule can be complementary to two (or even more) non-contiguous substrate sequences or two (or even more) non-contiguous sequence portions of an antisense molecule can be complementary to a target sequence or both.
By "consists essentially of is meant that the active nucleic acid molecule of the invention, for example, an enzymatic nucleic acid molecule, contains an enzymatic center or core equivalent to those in the examples, and binding arms able to bind RNA such that cleavage at the target site occurs. Other sequences can be present that do not interfere with such cleavage. Thus, a core region can, for example, include one or more loop, stem-loop structure, or linker which does not prevent enzymatic activity. Thus, the underlined regions in the sequences in Tables III, IV, VIII, IX, XIII, XIV, XIX, and XX can be such a loop, stem-loop, nucleotide linker, and/or non-nucleotide linker and can be represented generally as sequence "X". For example, a core sequence for a hammerhead enzymatic nucleic acid can comprise a conserved sequence, such as 5'-CUGAUGAG-3' and 5'-CGAA-3' connected by "X", where X is 5'-GCCGUUAGGC-3' (SEQ ID NO: 13274), or any other Stem fl region known in the art, or a nucleotide and or non-nucleotide linker. Similarly, for other nucleic acid molecules of the instant invention, such as Inozyme, G-cleaver, amberzyme, zinzyme, DNAzyme, antisense, 2-5A antisense, triplex forming nucleic acid, siRNA and decoy nucleic acids, other sequences or non-nucleotide linkers can be present that do not interfere with the function ofthe nucleic acid molecule.
Sequence X can be a linker of > 2 nucleotides in length, including 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 26, 30, where the nucleotides can be internally base-paired to form a stem of > 2 base pairs. Alternatively or in addition, sequence X can be a non-nucleotide linker. In yet another embodiment, the nucleotide linker X can be a nucleic acid aptamer, such as an ATP aptamer, HIV Rev aptamer (RRE), HIV Tat aptamer (TAR) and others (for a review see Gold et al, 1995, Annu. Rev. Biochem., 64, 763; and Szostak & Ellington, 1993, in The RNA World, ed. Gesteland and Atkins, pp. 511, CSH Laboratory Press). A "nucleic acid aptamer" as used herein is meant to indicate a nucleic acid sequence capable of interacting with a ligand. The ligand can be any natural or a synthetic molecule, including but not limited to a resin, metabolites, nucleosides, nucleotides, dmgs, toxins, transition state analogs, peptides, lipids, proteins, amino acids, nucleic acid molecules, hormones, carbohydrates, receptors, cells, viruses, bacteria and others.
In yet another embodiment, the non-nucleotide linker X is as defined herein. The term "non-nucleotide" as used herein include either abasic nucleotide, polyether, polyamine, polyamide, peptide, carbohydrate, lipid, or polyhydrocarbon compounds. Specific examples include those described by Seela and Kaiser, Nucleic Acids Res. 1990, 7S:6353 and Nucleic Acids Res. 1987, 75:3113; Cload and Schepartz, J. Am. Chem. Soc. 1991, 773:6324; Richardson and Schepartz, J. Am. Chem. Soc. 1991, 773:5109; Ma et al, Nucleic Acids Res. 1993, 27:2585 and Biochemistry 1993, 32:1751; Durand et al. Nucleic Acids Res. 1990, 75:6353; McCurdy et al, Nucleosides & Nucleotides 1991, 70:287; Jschke et al, Tetrahedron Lett. 1993, 34:301; Ono et al, Biochemistry 1991, 30:9914; Arnold et al, International Publication No. WO 89/02439; Usman et al, International Publication No. WO 95/06731; Dudycz et al, International Publication No. WO 95/11910 and Ferentz and Verdine, J. Am. Chem. Soc. 1991, 773:4000, all hereby incoφorated by reference herein. A "non-nucleotide" further means any group or compound that can be incorporated into a nucleic acid chain in the place of one or more nucleotide units, including either sugar and/or phosphate substitutions, and allows the remaining bases to exhibit their enzymatic activity. The group or compound can be abasic in that it does not contain a commonly recognized nucleotide base, such as adenosine, guanine, cytosine, uracil or thymine. Thus, in a preferred embodiment, the invention features an enzymatic nucleic acid molecule having one or more non-nucleotide moieties, and having enzymatic activity to cleave an RNA or DNA molecule. In another aspect of the invention, nucleic acid molecules that interact with target RNA molecules and down-regulate target genes (e.g., prostaglandin D2 receptor (PTGDR), prostaglandin D2 synthetase (PTGDS), adenosine receptors (AR) such as adenosine receptor Al (ADORAl), A2a, A2b, and A3, NOGO-A, NOGO-B, NOGO-C, NI-35, NI-220, NI-250, myelin-associated glycoprotein, tenascin-R, NG-2 and/or their corresponding receptors, an DcappaB kinase (IKK) subunit and or protein kinase PKR gene) activity are expressed from transcription units inserted into DNA or RNA vectors. The recombinant vectors can be DNA plasmids or viral vectors. Enzymatic nucleic acid molecule or antisense expressing viral vectors can be constmcted based on, but not limited to, adeno-associated vims, retrovirus, adenovims, or alphavims. The recombinant vectors capable of expressing the enzymatic nucleic acid molecules or antisense can be delivered as described above, and persist in target cells. Alternatively, viral vectors can be used that provide for transient expression of enzymatic nucleic acid molecules or antisense. Such vectors can be repeatedly administered as necessary. Once expressed, the enzymatic nucleic acid molecules or antisense bind to the target RNA and down-regulate its function or expression. Delivery of enzymatic nucleic acid molecule or antisense expressing vectors can be systemic, such as by intravenous or intramuscular administration, by administration to target cells ex-planted from the patient followed by reintroduction into the patient, or by any other means that would allow for introduction into the desired target cell. Antisense DNA can be expressed via the use of a single stranded DNA intracellular expression vector.
By "vectors" is meant any nucleic acid- and/or viral-based technique used to deliver a desired nucleic acid.
By "patient" is meant an organism, which is a donor or recipient of explanted cells, or the cells themselves. "Patient" also refers to an organism to which the nucleic acid molecules of the invention can be administered. A patient can be a mammal or mammalian cells. In one embodiment, a patient is a human or human cells.
By "enhanced enzymatic activity" is meant to include activity measured in cells and/or in vivo where the activity is a reflection of both the catalytic activity and the stability of the nucleic acid molecules of the invention. In this invention, the product of these properties can be increased in vivo compared to an all RNA enzymatic nucleic acid or all DNA enzyme. In some cases, the activity or stability of the nucleic acid molecule can be decreased (i.e., less than ten- fold), but the overall activity ofthe nucleic acid molecule is enhanced, in vivo.
The nucleic acid molecules of the instant invention, individually, or in combination or in conjunction with other dmgs, can be used to treat diseases or conditions discussed above. For example, to treat a disease or condition associated with the levels of prostaglandin D2 receptor (PTGDR), prostaglandin D2 synthetase (PTGDS), adenosine receptors (AR) such as adenosine receptor Al (ADORAl), A2a, A2b, and A3, NOGO-A, NOGO-B, NOGO-C, NI- 35, NI-220, NI-250, myelin-associated glycoprotein, tenascin-R, NG-2 and/or their corresponding receptors, an DcappaB kinase (IKK) subunit and/or protein kinase PKR, the patient can be treated, or other appropriate cells can be treated, as is evident to those skilled in the art, individually or in combination with one or more drugs under conditions suitable for the treatment.
In a further embodiment, the described molecules, such as antisense or enzymatic nucleic acid molecules, can be used in combination with other known treatments to treat conditions or diseases discussed above. For example, the described molecules can be used in combination with one or more known therapeutic agents to treat allergic diseases or conditions, including but not limited to asthma, allergic rhinitis, atopic dermatitis, and/or other allergic or inflammatory diseases and conditions which respond to the modulation of prostaglandin D2 receptor (PTGDR), prostaglandin D2 synthetase (PTGDS), adenosine receptors (AR) such as adenosine receptor Al (ADORAl), A2a, A2b, and A3, NOGO-A, NOGO-B, NOGO-C, NI-35, NI-220, NI-250, myelin-associated glycoprotein, tenascin-R, NG-2 and/or their corresponding receptors, an DcappaB kinase (IKK) subunit and/or protein kinase PKR expression.
By "comprising" is meant including, but not limited to, whatever follows the word "comprising". Thus, use of the term "comprising" indicates that the listed elements are required or mandatory, but that other elements are optional and may or may not be present. By "consisting of is meant including, and limited to, whatever follows the phrase "consisting of. Thus, the phrase "consisting of indicates that the listed elements are required or mandatory, and that no other elements may be present.
Other features and advantages of the invention will be apparent from the following description ofthe preferred embodiments thereof, and from the claims.
Brief Description ofthe Drawings
Figure 1 shows examples of chemically stabilized ribozyme motifs. HH Rz, represents hammerhead ribozyme motif (Usman et al, 1996, Curr. Op. Struct. Bio., 1, 527); NCH Rz represents the NCH ribozyme motif (Ludwig & Sproat, International PCT Publication No. WO 98/58058); G-Cleaver, represents G-cleaver ribozyme motif (Kore et al, 1998, Nucleic Acids Research 26, 4116-4120, Eckstein et al, International PCT publication No. WO 99/16871). N or n, represent independently a nucleotide that can be same or different and have complementarity to each other; ri, represents ribo-Inosine nucleotide; arrow indicates the site of cleavage within the target. Position 4 of the HH Rz and the NCH Rz is shown as having 2'-C-allyl modification, but those skilled in the art will recognize that this position can be modified with other modifications well known in the art, so long as such modifications do not significantly inhibit the activity ofthe ribozyme.
Figure 2 shows an example of the Amberzyme ribozyme motif that is chemically stabilized (see for example Beigelman et al, International PCT publication No. WO 99/55857).
Figure 3 shows an example of the Zinzyme A ribozyme motif that is chemically stabilized (see for example Beigelman et al, Beigelman et al, International PCT publication No. WO 99/55857).
Figure 4 shows an example of a specific DNAzyme motif, commonly referred to as the
"10-23 motif, as described by Santoro et al, 1997, PNAS, 94, 4262.
Description ofthe Preferred Embodiments
Nucleic Acid Molecules and Mechanism of Action
Antisense: Antisense molecules can be modified or unmodified RNA, DNA, or mixed polymer oligonucleotides and primarily function by specifically binding to matching sequences resulting in inhibition of peptide synthesis (Wu-Pong, Nov 1994, BioPharm, 20- 33). The antisense oligonucleotide binds to target RNA by Watson Crick base-pairing and blocks gene expression by preventing ribosomal translation of the bound sequences either by steric blocking or by activating RNase H enzyme. Antisense molecules can also alter protein synthesis by interfering with RNA processing or transport from the nucleus into the cytoplasm (Mukhopadhyay & Roth, 1996, Crit. Rev. in Oncogenesis 1, 151-190).
In addition, binding of single stranded DNA to RNA can result in nuclease degradation of the heteroduplex (Wu-Pong, supra; Crooke, supra). To date, the only backbone modified
DNA chemistry which act as substrates for RNase H are phosphorothioates, phosphorodithioates, and borontrifluoridates. Recently it has been reported that 2'-arabino and 2 '-fluoro arabino- containing oligos can also activate RNase H activity.
A number of antisense molecules have been described that utilize novel configurations of chemically modified nucleotides, secondary stmcture, and/or RNase H substrate domains
(Woolf et al, International PCT Publication No. WO 98/13526; Thompson et al, International PCT Publication No. WO 99/54459; Hartmann et al, USSN 60/101,174, filed on September 21, 1998) all of these are incorporated by reference herein in their entirety.
In addition, antisense deoxyoligoribonucleotides can be used to target RNA by means of DNA-RNA interactions, thereby activating RNase H, which digests the target RNA in the duplex. Antisense DNA can be expressed via the use of a single stranded DNA intracellular expression vector or equivalents and variations thereof.
Triplex Forming Oligonucleotides (TFO): Single stranded DNA can be designed to bind to genomic DNA in a sequence specific manner. TFOs are comprised of pyrimidine-rich oligonucleotides which bind DNA helices through Hoogsteen Base-pairing (Wu-Pong, supra). The resulting triple helix composed of the DNA sense, DNA antisense, and TFO dismpts RNA synthesis by RNA polymerase. The TFO mechanism can result in gene expression or cell death since binding can be irreversible (Mukhopadhyay & Roth, supra).
2-5A Antisense Chimera: The 2-5A system is an interferon mediated mechanism for RNA degradation found in higher vertebrates (Mitra et al, 1996, Proc Nat Acad Sci USA 93, 6780-6785). Two types of enzymes, 2-5A synthetase and RNase L, are required for RNA cleavage. The 2-5A synthetases require double stranded RNA to form 2'-5' oligoadenylates (2-5 A). 2-5A then acts as an allosteric effector for utilizing RNase L, which has the ability to cleave single stranded RNA. The ability to form 2-5A stmctures with double stranded RNA makes this system particularly useful for inhibition of viral replication.
(2'-5') oligoadenylate stmctures can be covalently linked to antisense molecules to form chimeric oligonucleotides capable of RNA cleavage (Torrence, supra). These molecules putatively bind and activate a 2-5A dependent RNase, the oligonucleotide/enzyme complex then binds to a target RNA molecule which can then be cleaved by the RNase enzyme.
Aptamer: Nucleic acid aptamers can be selected to specifically bind to a particular ligand of interest (see for example Gold et al, US 5,567,588 and US 5,475,096, Gold et al, 1995, Annu. Rev. Biochem., 64, 763; Brody and Gold, 2000, J. Biotechnol, 14, 5; Sun, 2000, Curr. Opin. Mol. Ther., 2, 100; Kusser, 2000, J. Biotechnol, 74, 27; Hermann and Patel, 2000, Science, 287, 820; and Jayasena, 1999, Clinical Chemistry, 45, 1628). For example, the use of in vitro selection can be applied to evolve nucleic acid aptamers with binding specificity for the NOGO receptor, prostaglandin D2 receptor (PTGDR), adenosine receptors (AR) such as adenosine receptor Al (ADORAl), A2a, A2b, and A3, NOGO-A, NOGO-B, NOGO-C, NI-35, NI-220, NI-250, myelin-associated glycoprotein, tenascin-R, NG-2 and/or their corresponding receptors. Nucleic acid aptamers can include chemical modifications and linkers as described herein. Aptamer molecules of the invention that bind to a cellular receptor, such as prostaglandin D2 receptor (PTGDR), adenosine receptors (AR) such as adenosine receptor Al (ADORAl), A2a, A2b, and A3, NOGO-A, NOGO-B, NOGO-C, NI- 35, NI-220, NI-250, myelin-associated glycoprotein, tenascin-R, NG-2 and/or their corresponding receptors, or protein kinase PKR receptor, and modulate the activity of the receptor or ligand having specificity for the receptor. RNAi: RNA interference refers to the process of sequence specific post transcriptional gene silencing in animals mediated by short interfering RNAs (siRNA) (Fire et al, 1998, Nature, 391, 806). The corresponding process in plants is commonly referred to as post transcriptional gene silencing or RNA silencing and is also referred to as quelling in fungi. The process of post transcriptional gene silencing is thought to be an evolutionarily conserved cellular defense mechanism used to prevent the expression of foreign genes which is commonly shared by diverse flora and phyla (Fire et al, 1999, Trends Genet., 15, 358). Such protection from foreign gene expression may have evolved in response to the production of double stranded RNAs (dsRNA) derived from viral infection or the random integration of transposon elements into a host genome via a cellular response that specifically destroys homologous single stranded RNA or viral genomic RNA. The presence of dsRNA in cells triggers the RNAi response though a mechanism that has yet to be fully characterized. This mechanism appears to be different from the interferon response that results from dsRNA mediated activation of protein kinase PKR and 2',5'-oligoadenylate synthetase resulting in non-specific cleavage of mRNA by ribonuclease L.
The presence of long dsRNAs in cells stimulates the activity of a ribonuclease rn enzyme referred to as dicer. Dicer is involved in the processing of the dsRNA into short pieces of dsRNA known as short interfering RNAs (siRNA) (Berstein et al, 2001, Nature, 409, 363). Short interfering RNAs derived from dicer activity are typically about 21-23 nucleotides in length and comprise about 19 base pair duplexes. Dicer has also been implicated in the excision of 21 and 22 nucleotide small temporal RNAs (stRNA) from precursor RNA of conserved stmcture that are implicated in translational control (Hutvagner et al, 2001, Science, 293, 834). The RNAi response also features an endonuclease complex containing a siRNA, commonly referred to as an RNA-induced silencing complex (RISC), which mediates cleavage of single stranded RNA having sequence homologous to the siRNA. Cleavage of the target RNA takes place in the middle of the region complementary to the guide sequence ofthe siRNA duplex (Elbashir et al, 2001, Genes Dev., 15, 188).
Short interfering RNA mediated RNAi has been studied in a variety of systems. Fire et al, 1998, Nature, 391, 806, were the first to observe RNAi in C. Elegans. Wianny and Goetz, 1999, Nature Cell Biol, 2, 70, describes RNAi mediated by dsRNA in mouse embryos. Hammond et al, 2000, Nature, 404, 293, describe RNAi in Drosophila cells transfected with dsRNA. Elbashir et al, 2001, Nature, 411, 494, describe RNAi induced by introduction of duplexes of synthetic 21 -nucleotide RNAs in cultured mammalian cells including human embryonic kidney and HeLa cells. Recent work in Drosophila embryonic lysates has revealed certain requirements for siRNA length, stmcture, chemical composition, and sequence that are essential to mediate efficient RNAi activity. These studies have shown that 21 nucleotide siRNA duplexes are most active when containing two nucleotide 3'- overhangs. Furthermore, substitution of one or both siRNA strands with 2'-deoxy or 2'-O- methyl nucleotides abolishes RNAi activity, whereas substitution of 3 '-terminal siRNA nucleotides with deoxy nucleotides was shown to be tolerated. Mismatch sequences in the center of the siRNA duplex were also shown to abolish RNAi activity. In addition, these studies also indicate that the position of the cleavage site in the target RNA is defined by the 5'-end of the siRNA guide sequence rather than the 3'-end (Elbashir et al, 2001, EMBO J., 20, 6877). Other studies have indicated that a 5 '-phosphate on the target-complementary strand of a siRNA duplex is required for siRNA activity and that ATP is utilized to maintain the 5'-phosphate moiety on the siRNA (Nykanen et al, 2001, Cell, 107, 309), however siRNA molecules lacking a 5 '-phosphate are active when introduced exogenously, suggesting that 5 '-phosphorylation of siRNA constructs may occur in vivo.
Enzymatic Nucleic Acid: Several varieties of naturally-occurring enzymatic RNAs are presently known. In addition, several in vitro selection (evolution) strategies (Orgel, 1979, Proc. R. Soc. London, B 205, 435) have been used to evolve new nucleic acid catalysts capable of catalyzing cleavage and ligation of phosphodiester linkages (Joyce, 1989, Gene, 82, 83-87; Beaudry et al, 1992, Science 257, 635-641 ; Joyce, 1992, Scientific American 267, 90-97; Breaker et al, 1994, TIBTECH 12, 268; Bartel et α/., 1993, Science 261 :1411-1418; Szostak, 1993, T773S 17, 89-93; Kumar et al, 1995, FASEB J., 9, 1183; Breaker, 1996, Curr. Op. Biotech., 1, 442; Santoro et al, 1997, Proc. Natl. Acad. Sci., 94, 4262; Tang et al, 1997, RNA 3, 914; Nakamaye & Eckstein, 1994, supra; Long & Uhlenbeck, 1994, supra; Ishizaka et al, 1995, supra; Vaish et al, 1997, Biochemistry 36, 6495; all of these are incoφorated by reference herein). Each can catalyze a series of reactions including the hydrolysis of phosphodiester bonds in trans (and thus can cleave other RNA molecules) under physiological conditions.
The enzymatic nature of an enzymatic nucleic acid molecule has significant advantages, one advantage being that the concentration of enzymatic nucleic acid molecule necessary to affect a therapeutic treatment is lower. This advantage reflects the ability of the enzymatic nucleic acid molecule to act enzymatically. Thus, a single enzymatic nucleic acid molecule is able to cleave many molecules of target RNA. In addition, the enzymatic nucleic acid molecule is a highly specific inhibitor, with the specificity of inhibition depending not only on the base-pairing mechanism of binding to the target RNA, but also on the mechanism of target RNA cleavage. Single mismatches, or base-substitutions, near the site of cleavage can be chosen to completely eliminate catalytic activity of a enzymatic nucleic acid molecule.
Nucleic acid molecules having an endonuclease enzymatic activity are able to repeatedly cleave other separate RNA molecules in a nucleotide base sequence-specific manner. With the proper design, such enzymatic nucleic acid molecules can be targeted to
RNA transcripts, and achieve efficient cleavage in vitro (Zaug et al, 324, Nature 429 1986;
Uhlenbeck, 1987 Nature 328, 596; Kim et al, 84 Proc. Natl. Acad. Sci. USA 8788, 1987; Dreyfus, 1988, Einstein Quart. J. Bio. Med., 6, 92; Haseloff and Gerlach, 334 Nature 585, 1988; Cech, 260 JAMA 3030, 1988; and Jefferies et al, 17 Nucleic Acids Research 1371, 1989; Santoro et al, 1997 supra).
Because of their sequence specificity, trans-cleaving enzymatic nucleic acid molecules can be used as therapeutic agents for human disease (Usman & McSwiggen, 1995 Ann. Rep. Med. Chem. 30, 285-294; Christoffersen and Marr, 1995 J. Med. Chem. 38, 2023-2037). Enzymatic nucleic acid molecules can be designed to cleave specific RNA targets within the background of cellular RNA. Such a cleavage event renders the RNA non-functional and abrogates protein expression from that RNA. In this manner, synthesis of a protein associated with a disease state can be selectively inhibited (Warashina et al, 1999, Chemistry and Biology, 6, 237-250).
Enzymatic nucleic acid molecules of the invention that are allosterically regulated ("allozymes") can be used to down-regulate prostaglandin D2 receptor (PTGDR), prostaglandin D2 synthetase (PTGDS), adenosine receptors (AR) such as adenosine receptor Al (ADORAl), A2a, A2b, and A3, NOGO-A, NOGO-B, NOGO-C, NI-35, NI-220, NI-250, myelin-associated glycoprotein, tenascin-R, NG-2 and/or their corresponding receptors, an DcappaB kinase (IKK) subunit and/or protein kinase PKR expression. These allosteric enzymatic nucleic acids or allozymes (see for example George et al, US Patent Nos. 5,834,186 and 5,741,679, Shih et al, US Patent No. 5,589,332, Nathan et al, US Patent No 5,871,914, Nathan and Ellington, International PCT publication No. WO 00/24931, Breaker et al, International PCT Publication Nos. WO 00/26226 and 98/27104, and Sullenger et al, International PCT publication No. WO 99/29842) are designed to respond to a signaling agent, for example, mutant and/or wild type protein, other proteins and/or RNAs involved in target gene signal transduction, compounds, metals, polymers, molecules and/or dmgs that are targeted to target gene expressing cells etc., which in turn modulates the activity of the enzymatic nucleic acid molecule. In response to interaction with a predetermined signaling agent, the allosteric enzymatic nucleic acid molecule's activity is activated or inhibited such that the expression of a particular target is selectively down-regulated. The target can comprise wild-type protein, mutant protein, and/or a predetermined component of the protein's signal transduction pathway. In a specific example, allosteric enzymatic nucleic acid molecules that are activated by interaction with a RNA encoding a PTGDR protein are used as therapeutic agents in vivo. The presence of RNA encoding the PTGDS protein activates the allosteric enzymatic nucleic acid molecule that subsequently cleaves the RNA encoding a PTGDR protein resulting in the inhibition of PTGDR protein expression. In this manner, cells that express both PTGDS and PTGDR protein are selectively targeted.
In another non-limiting example, an allozyme can be activated by a prostaglandin D2 receptor (PTGDR), prostaglandin D2 synthetase (PTGDS), adenosine receptors (AR) such as adenosine receptor Al (ADORAl), A2a, A2b, and A3, NOGO-A, NOGO-B, NOGO-C, NI- 35, NI-220, NI-250, myelin-associated glycoprotein, tenascin-R, NG-2 and/or their corresponding receptors, an DcappaB kinase (IKK) subunit and/or protein kinase PKR protein, peptide, or mutant polypeptide that causes the allozyme to inhibit the expression of a target gene, by, for example, cleaving RNA encoded by the target gene. In this non-limiting example, the allozyme acts as a decoy to inhibit the function of the target protein and also inhibit the expression of the protein once activated by the prostaglandin D2 receptor (PTGDR), prostaglandin D2 synthetase (PTGDS), adenosine receptors (AR) such as adenosine receptor Al (ADORAl), A2a, A2b, and A3, NOGO-A, NOGO-B, NOGO-C, NI- 35, NI-220, NI-250, myelin-associated glycoprotein, tenascin-R, NG-2 and/or their corresponding receptors, an DcappaB kinase (IKK) subunit and/or protein kinase PKR protein.
Target sites
Targets for useful enzymatic nucleic acid molecules and antisense nucleic acids can be determined as disclosed in Draper et al, WO 93/23569; Sullivan et al, WO 93/23057; Thompson et al, WO 94/02595; Draper et al, WO 95/04818; McSwiggen et al, US Patent No. 5,525,468, and hereby incoφorated by reference herein in totality. Other examples include the following PCT applications, which concern inactivation of expression of disease- related genes: WO 95/23225, WO 95/13380, WO 94/02595, incoφorated by reference herein. Rather than repeat the guidance provided in those documents here, below are provided specific examples of such methods, not limiting to those in the art. Enzymatic nucleic acid molecules and antisense to such targets are designed as described in those applications and synthesized to be tested in vitro and in vivo, as also described. The sequences of human prostaglandin D2 receptor (PTGDR), prostaglandin D2 synthetase (PTGDS), adenosine receptors (AR) such as adenosine receptor Al (ADORAl), A2a, A2b, and A3, NOGO-A, NOGO-B, NOGO-C, NI-35, NI-220, NI-250, myelin-associated glycoprotein, tenascin-R, NG-2 and/or their corresponding receptors, an DcappaB kinase (IKK) subunit and/or protein kinase PKR RNAs were screened for optimal enzymatic nucleic acid and antisense target sites using a computer-folding algorithm. Antisense, hammerhead, DNAzyme, NCH, amberzyme, zinzyme, or G-Cleaver enzymatic nucleic acid molecule binding/cleavage sites were identified. These sites are shown in Tables III to XXIII (all sequences are 5' to 3' in the tables; underlined regions can be any sequence "X" or linker X, the actual sequence is not relevant here). The nucleotide base position is noted in the Tables as that site to be cleaved by the designated type of enzymatic nucleic acid molecule. While human sequences can be screened and enzymatic nucleic acid molecule and/or antisense thereafter designed, as discussed in Stinchcomb et al, WO 95/23225, mouse targeted enzymatic nucleic acid molecules can be useful to test efficacy of action of the enzymatic nucleic acid molecule and/or antisense prior to testing in humans. Antisense, siRNA, hammerhead, DNAzyme, NCH, amberzyme, zinzyme or G-Cleaver enzymatic nucleic acid molecule binding/cleavage sites were identified. The nucleic acid molecules are individually analyzed by computer folding (Jaeger et al, 1989 Proc. Natl. Acad. Sci. USA, 86, 7706) to assess whether the sequences fold into the appropriate secondary stmcture. Those nucleic acid molecules with unfavorable intramolecular interactions such as between the binding arms and the catalytic core are eliminated from consideration. Varying binding arm lengths can be chosen to optimize activity.
Antisense, siRNA, hammerhead, DNAzyme, NCH, amberzyme, zinzyme or G-Cleaver enzymatic nucleic acid molecule binding/cleavage sites were identified and were designed to anneal to various sites in the RNA target. The binding arms are complementary to the target site sequences described above. The nucleic acid molecules were chemically synthesized. The method of synthesis used follows the procedure for normal DNA/RNA synthesis as described below and in Usman et al, 1987 J. Am. Chem. Soc, 109, 7845; Scaringe et al, 1990 Nucleic Acids Res., 18, 5433; and Wincott et al, 1995 Nucleic Acids Res. 23, 2677- 2684; Caruthers et al, 1992, Methods in Enzymology 211,3-19.
Synthesis of Nucleic acid Molecules
Synthesis of nucleic acids greater than 100 nucleotides in length is difficult using automated methods, and the therapeutic cost of such molecules is prohibitive. In this invention, small nucleic acid motifs ("small refers to nucleic acid motifs less than about 100 nucleotides in length, and in one embodiment less than about 80 nucleotides in length, and in another embodiment less than about 50 nucleotides in length; e.g., antisense oligonucleotides, hammerhead or the NCH ribozymes) can be used for exogenous delivery. The simple stmcture of these molecules increases the ability of the nucleic acid to invade targeted regions of RNA stmcture. Exemplary molecules of the instant invention are chemically synthesized, and others can similarly be synthesized.
Oligonucleotides (e.g., antisense GeneBlocs) are synthesized using protocols known in the art as described in Camthers et al, 1992, Methods in Enzymology 211, 3-19, Thompson et al, International PCT Publication No. WO 99/54459, Wincott et al, 1995, Nucleic Acids Res. 23, 2677-2684, Wincott et al, 1997, Methods Mol. Bio., 74, 59, Brennan et al, 1998, Biotechnol Bioeng., 61, 33-45, and Brennan, US patent No. 6,001,311. All of these references are incoφorated herein by reference. The synthesis of oligonucleotides makes use of common nucleic acid protecting and coupling groups, such as dimethoxytrityl at the 5'-end, and phosphoramidites at the 3'-end. In a non-limiting example, small scale syntheses are conducted on a 394 Applied Biosystems, Inc. synthesizer using a 0.2 μmol scale protocol with a 2.5 min coupling step for 2'-O-methylated nucleotides and a 45 sec coupling step for 2'-deoxy nucleotides. Table II outlines the amounts and the contact times of the reagents used in the synthesis cycle. Alternatively, syntheses at the 0.2 μmol scale can be performed on a 96-well plate synthesizer, such as the instmment produced by Protogene (Palo Alto, CA) with minimal modification to the cycle. A 33-fold excess (60 μL of 0.11 M = 6.6 μmol) of 2'-O-methyl phosphoramidite and a 105-fold excess of S-ethyl tetrazole (60 μL of 0.25 M = 15 μmol) can be used in each coupling cycle of 2'-O-methyl residues relative to polymer- bound 5 '-hydroxyl. A 22-fold excess (40 μL of 0.11 M = 4.4 μmol) of deoxy phosphoramidite and a 70-fold excess of S-ethyl tetrazole (40 μL of 0.25 M = 10 μmol) can be used in each coupling cycle of deoxy residues relative to polymer-bound 5 '-hydroxyl. Average coupling yields on the 394 Applied Biosystems, Inc. synthesizer, determined by colorimetric quantitation ofthe trityl fractions, are typically 91.5-99%. Other oligonucleotide synthesis reagents for the 394 Applied Biosystems, Inc. synthesizer include; detritylation solution is 3% TCA in methylene chloride (ABI); capping is performed with 16% N-methyl imidazole in THF (ABI) and 10% acetic anhydride/10% 2,6-lutidine in THF (ABI); and oxidation solution is 16.9 mM h, 49 mM pyridine, 9% water in THF (PERSEPTIVE™). Burdick & Jackson Synthesis Grade acetonitrile is used directly from the reagent bottle. S- Ethyltetrazole solution (0.25 M in acetonitrile) is made up from the solid obtained from American International Chemical, Inc. Alternately, for the introduction of phosphorothioate linkages, Beaucage reagent (3H-l,2-Benzodithiol-3-one 1,1-dioxide, 0.05 M in acetonitrile) is used.
Deprotection of the antisense oligonucleotides is performed as follows: the polymer- bound trityl-on oligoribonucleotide is transferred to a 4 mL glass screw top vial and suspended in a solution of 40% aq. methylamine (1 mL) at 65 °C for 10 min. After cooling to -20 °C, the supernatant is removed from the polymer support. The support is washed three times with 1.0 mL of EtOH:MeCΝ:H2O/3:l :l, vortexed and the supernatant is then added to the first supernatant. The combined supematants, containing the oligoribonucleotide, are dried to a white powder.
The method of synthesis used for normal RNA including certain enzymatic nucleic acid molecules follows the procedure as described in Usman et al, 1987, J. Am. Chem. Soc, 109, 7845; Scaringe et al, 1990, Nucleic Acids Res., 18, 5433; and Wincott et al, 1995, Nucleic Acids Res. 23, 2677-2684 Wincott et al, 1997, Methods Mol. Bio., 74, 59, and makes use of common nucleic acid protecting and coupling groups, such as dimethoxytrityl at the 5 '-end, and phosphoramidites at the 3'-end. In a non-limiting example, small scale syntheses are conducted on a 394 Applied Biosystems, Inc. synthesizer using a 0.2 μmol scale protocol with a 7.5 min coupling step for alkylsilyl protected nucleotides and a 2.5 min coupling step for 2'-O-methylated nucleotides. Table II outlines the amounts and the contact times of the reagents used in the synthesis cycle. Alternatively, syntheses at the 0.2 μmol scale can be done on a 96-well plate synthesizer, such as the instmment produced by Protogene (Palo Alto, CA) with minimal modification to the cycle. A 33-fold excess (60 μL of 0.11 M = 6.6 μmol) of 2'-O-methyl phosphoramidite and a 75-fold excess of S-ethyl tetrazole (60 μL of 0.25 M = 15 μmol) can be used in each coupling cycle of 2 '-O-methyl residues relative to polymer- bound 5'-hydroxyl. A 66-fold excess (120 μL of 0.11 M = 13.2 μmol) of alkylsilyl (ribo) protected phosphoramidite and a 150-fold excess of S-ethyl tetrazole (120 μL of 0.25 M = 30 μmol) can be used in each coupling cycle of ribo residues relative to polymer-bound 5'- hydroxyl. Average coupling yields on the 394 Applied Biosystems, Inc. synthesizer, determined by colorimetric quantitation of the trityl fractions, are typically 91.5-99%. Other oligonucleotide synthesis reagents for the 394 Applied Biosystems, Inc. synthesizer include; detritylation solution is 3%> TCA in methylene chloride (ABI); capping is performed with 16% N-methyl imidazole in THF (ABI) and 10% acetic anhydride/10% 2,6-lutidine in THF (ABI); oxidation solution is 16.9 mM I2, 49 mM pyridine, 9% water in THF
(PERSEPTΓVE™). Burdick & Jackson Synthesis Grade acetonitrile is used directly from the reagent bottle. S-Ethyltetrazole solution (0.25 M in acetonitrile) is made up from the solid obtained from American International Chemical, Inc. Alternately, for the introduction of phosphorothioate linkages, Beaucage reagent (3H-l,2-Benzodithiol-3-one 1,1-dioxide 0.05 M in acetonitrile) is used.
Deprotection of the RΝA is performed using either a two-pot or one-pot protocol. For the two-pot protocol, the polymer-bound trityl-on oligoribonucleotide is transferred to a 4 mL glass screw top vial and suspended in a solution of 40% aq. methylamine (1 mL) at 65 °C for 10 min. After cooling to -20 °C, the supernatant is removed from the polymer support. The support is washed three times with 1.0 mL of EtOH:MeCΝ:H2O/3:l:l, vortexed and the supernatant is then added to the first supernatant. The combined supematants, containing the oligoribonucleotide, are dried to a white powder. The base deprotected oligoribonucleotide is resuspended in anhydrous TEA/HF/NMP solution (300 μL of a solution of 1.5 mL N- methylpyrrolidinone, 750 μL TEA and 1 mL TEA»3HF to provide a 1.4 M HF concentration) and heated to 65 °C. After 1.5 h, the oligomer is quenched with 1.5 M NH4HCO3.
Alternatively, for the one-pot protocol, the polymer-bound trityl-on oligoribonucleotide is transferred to a 4 mL glass screw top vial and suspended in a solution of 33% ethanolic methylamine/DMSO: 1/1 (0.8 mL) at 65 °C for 15 min. The vial is brought to r.t. TEAβHF
(0.1 mL) is added and the vial is heated at 65 °C for 15 min. The sample is cooled at -20 °C and then quenched with 1.5 M NH4HCO3.
For purification of the trityl-on oligomers, the quenched NH4HCO3 solution is loaded onto a C-18 containing cartridge that had been prewashed with acetonitrile followed by 50 mM TEAA. After washing, the loaded cartridge with water, the RNA is detritylated with
0.5%) TFA for 13 min. The cartridge is then washed again with water, salt exchanged with 1 M NaCl and washed with water again. The oligonucleotide is then eluted with 30% acetonitrile.
Inactive hammerhead ribozymes or binding attenuated control (BAC) oligonucleotides are synthesized by substituting a U for G5 and a U for A14 (numbering from Hertel, K. J., et al, 1992, Nucleic Acids Res., 20, 3252). Similarly, one or more nucleotide substitutions can be introduced in other enzymatic nucleic acid molecules to inactivate the molecule and such molecules can serve as a negative control.
The average stepwise coupling yields are typically >98% (Wincott et al, 1995 Nucleic
Acids Res. 23, 2677-2684). Those of ordinary skill in the art will recognize that the scale of synthesis can be adapted to be larger or smaller than the example described above including but not limited to 96 well format, all that is important is the ratio of chemicals used in the reaction.
Alternatively, the nucleic acid molecules of the present invention can be synthesized separately and joined together post-synthetically, for example by ligation (Moore et al, 1992, Science 256, 9923; Draper et al, International PCT publication No. WO 93/23569;
Shabarova et al, 1991, Nucleic Acids Research 19, 4247; Bellon et al, 1997, Nucleosides &
Nucleotides, 16, 951; Bellon et al, 1997, Bioconjugate Chem. 8, 204).
The nucleic acid molecules of the present invention can be modified extensively to enhance stability by modification with nuclease resistant groups, for example, 2'-amino, 2'-C- allyl, 2'-flouro, 2'-O-methyl, 2'-H (for a review see Usman and Cedergren, 1992, TIBS 17, 34; Usman et al, 1994, Nucleic Acids Symp. Ser. 31, 163). Ribozymes are purified by gel electrophoresis using general methods or are purified by high pressure liquid chromatography (HPLC; See Wincott et al, Supra, the totality of which is hereby incoφorated herein by reference) and are re-suspended in water. The sequences of the nucleic acid molecules, including enzymatic nucleic acid molecules and antisense, that are chemically synthesized, are shown in Tables III-XXIII. The sequences of the enzymatic nucleic acid constmcts that are chemically synthesized are complementary to the Substrate sequences shown in Tables III-XXIII. Those in the art will recognize that these sequences are representative only of many more such sequences where the enzymatic portion of the enzymatic nucleic acid (all but the binding arms) is altered to affect activity. The enzymatic nucleic acid constmct sequences listed in Tables III-XXIII can be formed of ribonucleotides or other nucleotides or non-nucleotides. Such enzymatic nucleic acid molecules with enzymatic activity are equivalent to the enzymatic nucleic acid molecules described specifically in the Tables. Optimizing Activity ofthe nucleic acid molecule ofthe invention.
Chemically synthesizing nucleic acid molecules with modifications (base, sugar and/or phosphate) that prevent their degradation by semm ribonucleases can increase their potency (see e.g., Eckstein et al, International Publication No. WO 92/07065; Perrault et al, 1990 Nature 344, 565; Pieken et al, 1991, Science 253, 314; Usman and Cedergren, 1992, Trends in Biochem. Sci. 17, 334; Usman et al, International Publication No. WO 93/15187; and Rossi et al, International Publication No. WO 91/03162; Sproat, US Patent No. 5,334,711; and Burgin et al, supra; all of these describe various chemical modifications that can be made to the base, phosphate and/or sugar moieties of the nucleic acid molecules herein). Modifications that enhance their efficacy in cells, and removal of bases from nucleic acid molecules to shorten oligonucleotide synthesis times and reduce chemical requirements are desired. (All these publications are hereby incoφorated by reference herein).
There are several examples in the art describing sugar, base and phosphate modifications that can be introduced into nucleic acid molecules with significant enhancement in their nuclease stability and efficacy. For example, oligonucleotides are modified to enhance stability and/or enhance biological activity by modification with nuclease resistant groups, for example, 2'-amino, 2'-C-allyl, 2'-flouro, 2'-O-methyl, 2'-H, nucleotide base modifications (for a review see Usman and Cedergren, 1992, 775S. 17, 34; Usman et al, 1994, Nucleic Acids Symp. Ser. 31, 163; Burgin et al, 1996, Biochemistry, 35, 14090). Sugar modification of nucleic acid molecules have been extensively described in the art (see Eckstein et al, International Publication PCT No. WΟ 92/07065; Perrault et al. Nature, 1990, 344, 565-568; Pieken et al. Science, 1991, 253, 314-317; Usman and Cedergren, Trends in Biochem. Sci. , 1992, 17, 334-339; Usman et al. International Publication PCT No. WO 93/15187; Sproat, US Patent No. 5,334,711 and Beigelman et al, 1995, J. Biol. Chem., 270, 25702; Beigelman et al, International PCT publication No. WO 97/26270; Beigelman et al, US Patent No. 5,716,824; Usman et al, US patent No. 5,627,053; Woolf et al, International PCT Publication No. WO 98/13526; Thompson et al, USSN 60/082,404 which was filed on April 20, 1998; Kaφeisky et al, 1998, Tetrahedron Lett., 39, 1131; Eamshaw and Gait, 1998, Biopolymers (Nucleic acid Sciences), 48, 39-55; Nerma and Eckstein, 1998, Annu. Rev. Biochem., 67, 99-134; and Burlina et al, 1997, Bioorg. Med. Chem., 5, 1999-2010; all of the references are hereby incoφorated in their totality by reference herein). Such publications describe general methods and strategies to determine the location of incoφoration of sugar, base and/or phosphate modifications and the like into ribozymes without inhibiting catalysis, and are incoφorated by reference herein. In view of such teachings, similar modifications can be used as described herein to modify the nucleic acid molecules ofthe instant invention. While chemical modification of oligonucleotide internucleotide linkages with phosphorothioate, phosphorothioate, and/or 5 '-methylphosphonate linkages improves stability, too many of these modifications can cause some toxicity. Therefore when designing nucleic acid molecules the amount of these internucleotide linkages should be minimized. The reduction in the concentration of these linkages should lower toxicity resulting in increased efficacy and higher specificity of these molecules.
Nucleic acid molecules having chemical modifications that maintain or enhance activity are provided. Such a nucleic acid is also generally more resistant to nucleases than an unmodified nucleic acid. Thus, in a cell and/or in vivo the activity may not be significantly lowered. Therapeutic nucleic acid molecules delivered exogenously are optimally stable within cells until translation of the target RNA has been inhibited long enough to reduce the levels ofthe undesirable protein. This period of time varies between hours to days depending upon the disease state. Clearly, nucleic acid molecules must be resistant to nucleases in order to function as effective intracellular therapeutic agents. Improvements in the chemical synthesis of RNA and DNA (Wincott et al, 1995 Nucleic Acids Res. 23, 2677; Caruthers et al, 1992, Methods in Enzymology 211, 3-19 (incoφorated by reference herein) have expanded the ability to modify nucleic acid molecules by introducing nucleotide modifications to enhance their nuclease stability as described above.
In one embodiment, nucleic acid molecules of the invention include one or more G- clamp nucleotides. A G-clamp nucleotide is a modified cytosine analog wherein modifications result in the ability to hydrogen bond both Watson-Crick and Hoogsteen faces of a complementary guanine within a duplex, see for example Lin and Matteucci, 1998, J. Am. Chem. Soc, 120, 8531-8532. A single G-clamp analog substation within an oligonucleotide can result in substantially enhanced helical thermal stability and mismatch discrimination when hybridized to complementary oligonucleotides. The inclusion of such nucleotides in nucleic acid molecules of the invention can enable both enhanced affinity and specificity to nucleic acid targets.
Therapeutic nucleic acid molecules {e.g., enzymatic nucleic acid molecules and antisense nucleic acid molecules) delivered exogenously are optimally stable within cells until translation of the target RNA has been inhibited long enough to reduce the levels of the undesirable protein. This period of time varies between hours to days depending upon the disease state. These nucleic acid molecules should be resistant to nucleases in order to function as effective intracellular therapeutic agents. Improvements in the chemical synthesis of nucleic acid molecules described in the instant invention and in the art have expanded the ability to modify nucleic acid molecules by introducing nucleotide modifications to enhance their nuclease stability as described above. In another embodiment, the invention features conjugates and/or complexes of nucleic acid molecules targeting prostaglandin D2 receptor (PTGDR), prostaglandin D2 synthetase (PTGDS), adenosine receptors (AR) such as adenosine receptor Al (ADORAl), A2a, A2b, and A3, NOGO-A, NOGO-B, NOGO-C, NI-35, NI-220, NI-250, myelin-associated glycoprotein, tenascin-R, NG-2 and/or their corresponding receptors, an DcappaB kinase (IKK) subunit and/or protein kinase PKR. Compositions and conjugates are used to facilitate delivery of molecules into a biological system, such as cells. The conjugates provided by the instant invention can impart therapeutic activity by transferring therapeutic compounds across cellular membranes, altering the pharmacokinetics, and/or modulating the localization of nucleic acid molecules of the invention. The present invention encompasses the design and synthesis of novel agents for the delivery of molecules, including but not limited to small molecules, lipids, phospholipids, nucleosides, nucleotides, nucleic acids, antibodies, toxins, negatively charged polymers and other polymers, for example proteins, peptides, hormones, carbohydrates, polyethylene glycols, or polyamines, across cellular membranes. In general, the transporters described are designed to be used either individually or as part of a multi- component system, with or without degradable linkers. These compounds are expected to improve delivery and/or localization of nucleic acid molecules of the invention into a number of cell types originating from different tissues, in the presence or absence of semm (see Sullenger and Cech, US 5,854,038). Conjugates of the molecules described herein can be attached to biologically active molecules via linkers that are biodegradable, such as biodegradable nucleic acid linker molecules.
The term "biodegradable nucleic acid linker molecule" as used herein, refers to a nucleic acid molecule that is designed as a biodegradable linker to connect one molecule to another molecule, for example, a biologically active molecule. The stability of the biodegradable nucleic acid linker molecule can be modulated by using various combinations of ribonucleotides, deoxyribonucleotides, and chemically modified nucleotides, for example 2'-O-methyl, 2'-fluoro, 2'-amino, 2'-O-amino, 2'-C-allyl, 2'-O-allyl, and other 2'-modified or base modified nucleotides. The biodegradable nucleic acid linker molecule can be a dimer, trimer, tetramer or longer nucleic acid molecule, for example an oligonucleotide of about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 nucleotides in length, or can comprise a single nucleotide with a phosphoms based linkage, for example a phosphoramidate or phosphodiester linkage. The biodegradable nucleic acid linker molecule can also comprise nucleic acid backbone, nucleic acid sugar, or nucleic acid base modifications.
The term "biodegradable" as used herein, refers to degradation in a biological system, for example enzymatic degradation or chemical degradation. The term "biologically active molecule" as used herein, refers to compounds or molecules that are capable of eliciting or modifying a biological response in a system. Non- limiting examples of biologically active molecules contemplated by the instant invention include therapeutically active molecules such as antibodies, hormones, antivirals, peptides, proteins, chemotherapeutics, small molecules, vitamins, co-factors, nucleosides, nucleotides, oligonucleotides, enzymatic nucleic acids, antisense nucleic acids, triplex forming oligonucleotides, 2,5-A chimeras, siRNA, dsRNA, allozymes, aptamers, decoys and analogs thereof. Biologically active molecules of the invention also include molecules capable of modulating the pharmacokinetics and/or pharmacodynamics of other biologically active molecules, for example lipids and polymers such as polyamines, polyamides, polyethylene glycol and other polyethers.
The term "phospholipid" as used herein, refers to a hydrophobic molecule comprising at least one phosphoms group. For example, a phospholipid can comprise a phosphoms containing group and saturated or unsaturated alkyl group, optionally substituted with OH, COOH, oxo, amine, or substituted or unsubstituted aryl groups.
In another embodiment, nucleic acid catalysts having chemical modifications that maintain or enhance enzymatic activity are provided. Such nucleic acids are also generally more resistant to nucleases than unmodified nucleic acids. Thus, in a cell and/or in vivo the activity of the nucleic acid may not be significantly lowered. As exemplified herein such enzymatic nucleic acids are useful in a cell and/or in vivo even if activity over all is reduced 10 fold (Burgin et al, 1996, Biochemistry, 35, 14090). Such enzymatic nucleic acids herein are said to "maintain" the enzymatic activity of an all RNA ribozyme or all DNA DNAzyme.
In another aspect the nucleic acid molecules comprise a 5' and/or a 3'- cap stmcture.
By "cap stmcture" is meant chemical modifications, which have been incoφorated at either terminus of the oligonucleotide (see for example Wincott et al, WO 97/26270, incoφorated by reference herein). These terminal modifications protect the nucleic acid molecule from exonuclease degradation, and can help in delivery and/or localization within a cell. The cap can be present at the 5 '-terminus (5 '-cap) or at the 3 '-terminus (3 '-cap) or can be present on both terminus. In non-limiting examples, the 5 '-cap includes inverted abasic residue (moiety), 4',5'-methylene nucleotide; l-(beta-D-erythrofuranosyl) nucleotide, 4'-thio nucleotide, carbocyclic nucleotide; 1,5-anhydrohexitol nucleotide; L-nucleo tides; alpha- nucleotides; modified base nucleotide; phosphorodithioate linkage; tbreo-pentofuranosyl nucleotide; acyclic 3',4'-seco nucleotide; acyclic 3,4-dihydroxybutyl nucleotide; acyclic 3,5- dihydroxypentyl nucleotide, 3 '-3 '-inverted nucleotide moiety; 3'-3'-inverted abasic moiety; 3'- 2'-inverted nucleotide moiety; 3'-2'-inverted abasic moiety; 1 ,4-butanediol phosphate; 3'- phosphoramidate; hexylphosphate; aminohexyl phosphate; 3 '-phosphate; 3 '-phosphorothioate; phosphorodithioate; or bridging or non-bridging methylphosphonate moiety (for more details see Wincott et al, International PCT publication No. WO 97/26270, incoφorated by reference herein).
In another embodiment the 3 '-cap includes, for example 4', 5 '-methylene nucleotide; 1- (beta-D-erythrofuranosyl) nucleotide; 4'-thio nucleotide, carbocyclic nucleotide; 5'-amino- alkyl phosphate; l,3-diamino-2-propyl phosphate, 3-aminopropyl phosphate; 6-aminohexyl phosphate; 1,2-aminododecyl phosphate; hydroxypropyl phosphate; 1,5-anhydrohexitol nucleotide; L-nucleotide; alpha-nucleotide; modified base nucleotide; phosphorodithioate; tbreo-pentofuranosyl nucleotide; acyclic 3',4'-seco nucleotide; 3,4-dihydroxybutyl nucleotide; 3,5-dihydroxypentyl nucleotide, 5'-5'-inverted nucleotide moiety; 5'-5'-inverted abasic moiety; 5'-phosphoramidate; 5'-phosphorothioate; 1 ,4-butanediol phosphate; 5'-amino; bridging and/or non-bridging 5'-phosphoramidate, phosphorothioate and/or phosphorodithioate, bridging or non bridging methylphosphonate and 5 '-mercapto moieties (for more details see Beaucage and Iyer, 1993, Tetrahedron 49, 1925; incoφorated by reference herein).
By the term "non-nucleotide" is meant any group or compound that can be incoφorated into a nucleic acid chain in the place of one or more nucleotide units, including either sugar and/or phosphate substitutions, and allows the remaining bases to exhibit their enzymatic activity. The group or compound is abasic in that it does not contain a commonly recognized nucleotide base, such as adenosine, guanine, cytosine, uracil or thymine.
An "alkyl" group refers to a saturated aliphatic hydrocarbon, including straight-chain, branched-chain, and cyclic alkyl groups. The alkyl group can have, for example, 1 to 12 carbons. In one embodiment of the invention, the alkyl group is a lower alkyl of from 1 to 7 carbons. In another embodiment the alkyl group is 1 to 4 carbons. The alkyl group can be substituted or unsubstituted. When substituted the substituted group(s) can be hydroxyl, cyano, alkoxy, =O, =S, NO2 or N(CH3)2, amino, or SH. The term also includes alkenyl groups which are unsaturated hydrocarbon groups containing at least one carbon-carbon double bond, including straight-chain, branched-chain, and cyclic groups. The alkenyl group can have, for example, 1 to 12 carbons. In one embodiment of the invention the alkenyl group can be a lower alkenyl of from 1 to 7 carbons. In another embodiment the alkenyl group can be 1 to 4 carbons. The alkenyl group can be substituted or unsubstituted. When substituted the substituted group(s) can be, for example, hydroxyl, cyano, alkoxy, =O, =S, NO2, halogen, N(CH )2, amino, or SH. The term "alkyl" also includes alkynyl groups which have an unsaturated hydrocarbon group containing at least one carbon-carbon triple bond, including straight-chain, branched-chain, and cyclic groups. , The alkynyl group can have, for example, 1 to 12 carbons. In one embodiment of the invention, the alkynyl group is a lower alkynyl of from 1 to 7 carbons. In another embodiment of the invention, the alkynyl group is 1 to 4 carbons. The alkynyl group can be substituted or unsubstituted. When substituted the substituted group(s) can be, for example, hydroxyl, cyano, alkoxy, =O, =S, NO2 or N(CH3)2, amino or SH.
Such alkyl groups can also include aryl, alkylaryl, carbocyclic aryl, heterocyclic aryl, amide and ester groups. An "aryl" group refers to an aromatic group which has at least one ring having a conjugated p electron system and includes carbocyclic aryl, heterocyclic aryl and biaryl groups, all of which can be optionally substituted. The preferred substituent(s) of aryl groups are halogen, trihalomethyl, hydroxyl, SH, OH, cyano, alkoxy, alkyl, alkenyl, alkynyl, and amino groups. An "alkylaryl" group refers to an alkyl group (as described above) covalently joined to an aryl group (as described above). Carbocyclic aryl groups are groups wherein the ring atoms on the aromatic ring are all carbon atoms. The carbon atoms are optionally substituted. Heterocyclic aryl groups are groups having from 1 to 3 heteroatoms as ring atoms in the aromatic ring and the remainder ofthe ring atoms are carbon atoms. Suitable heteroatoms include oxygen, sulfur, and nitrogen, and include furanyl, thienyl, pyridyl, pyrrolyl, N-lower alkyl pyrrolo, pyrimidyl, pyrazinyl, imidazolyl and the like, all optionally substituted. An "amide" refers to an -C(O)-NH-R, where R is either alkyl, aryl, alkylaryl or hydrogen. An "ester" refers to an -C(O)-OR', where R is either alkyl, aryl, alkylaryl or hydrogen.
By "nucleotide" is meant a heterocyclic nitrogenous base in N-glycosidic linkage with a phosphorylated sugar. Nucleotides are recognized in the art to include natural bases (standard), and modified bases well known in the art. Such bases are generally located at the 1' position of a nucleotide sugar moiety. Nucleotides generally comprise a base, sugar and a phosphate group. The nucleotides can be unmodified or modified at the sugar, phosphate and/or base moiety, (also referred to interchangeably as nucleotide analogs, modified nucleotides, non-natural nucleotides, non-standard nucleotides and other; see for example, Usman and McSwiggen, supra; Eckstein et al, International PCT Publication No. WO 92/07065; Usman et al, International PCT Publication No. WO 93/15187; Uhlman & Peyman, supra all are hereby incoφorated by reference herein). There are several examples of modified nucleic acid bases known in the art as summarized by Limbach et al, 1994, Nucleic Acids Res. 22, 2183. Some of the non-limiting examples of chemically modified and other natural nucleic acid bases that can be introduced into nucleic acids include, for example, inosine, purine, pyridin-4-one, pyridin-2-one, phenyl, pseudouracil, 2, 4, 6-trimethoxy benzene, 3-methyl uracil, dihydrouridine, naphthyl, aminophenyl, 5-alkylcytidines (e.g., 5-methylcytidine), 5-alkyluridines (e.g., ribothymidine), 5-halouridine (e.g., 5-bromouridine) or 6-azapyrimidines or 6-alkylpyrimidines (e.g. 6-methyluridine), propyne, quesosine, 2- thiouridine, 4-thiouridine, wybutosine, wybutoxosine, 4-acetylcytidine, 5- (carboxyhydroxymethyl)uridine, 5 '-carboxymethylaminomethyl-2-thiouridine, 5- carboxymethylaminomethyluridine, beta-D-galactosylqueosine, 1-methyladenosine, 1- methylinosine, 2,2-dimethylguanosine, 3-methylcytidine, 2-methyladenosine, 2- methylguanosine, N6-methyladenosine, 7-methylguanosine, 5-methoxyaminomethyl-2- thiouridine, 5-methylaminomethyluridine, 5-methylcarbonylmethyluridine, 5- methyloxyuridine, 5-methyl-2-thiouridine, 2-methylthio-N6-isopentenyladenosine, beta-D- mannosylqueosine, uridine-5-oxyacetic acid, 2-thiocytidine, threonine derivatives and others (Burgin et al, 1996, Biochemistry, 35, 14090; Uhlman & Peyman, supra). By "modified bases" in this aspect is meant nucleotide bases other than adenine, guanine, cytosine and uracil at 1' position or their equivalents; such bases can be used at any position, for example, within the catalytic core of an enzymatic nucleic acid molecule and/or in the substrate-binding regions ofthe nucleic acid molecule.
By "nucleoside" is meant a heterocyclic nitrogenous base in N-glycosidic linkage with a sugar. Nucleosides are recognized in the art to include natural bases (standard), and modified bases well known in the art. Such bases are generally located at the 1' position of a nucleoside sugar moiety. Nucleosides generally comprise a base and sugar group. The nucleosides can be unmodified or modified at the sugar, and/or base moiety, (also referred to interchangeably as nucleoside analogs, modified nucleosides, non-natural nucleosides, non- standard nucleosides and other; see for example, Usman and McSwiggen, supra; Eckstein et al, International PCT Publication No. WO 92/07065; Usman et al, International PCT Publication No. WO 93/15187; Uhlman & Peyman, supra all are hereby incoφorated by reference herein). There are several examples of modified nucleic acid bases known in the art as summarized by Limbach et al, 1994, Nucleic Acids Res. 22, 2183. Some of the non- limiting examples of chemically modified and other natural nucleic acid bases that can be introduced into nucleic acids include, inosine, purine, pyridin-4-one, pyridin-2-one, phenyl, pseudouracil, 2, 4, 6-trimethoxy benzene, 3-methyl uracil, dihydrouridine, naphthyl, aminophenyl, 5-alkylcytidines (e.g., 5-methylcytidine), 5-alkyluridines (e.g., ribothymidine), 5-halouridine (e.g., 5 -bromo uridine) or 6-azapyrimidines or 6-alkylpyrimidines (e.g. 6- methyluridine), propyne, quesosine, 2-thiouridine, 4-thiouridine, wybutosine, wybutoxosine, 4-acetylcytidine, 5-(carboxyhydroxymethyl)uridine, 5 '-carboxymethylaminomethyl-2- thiouridine, 5-carboxymethylaminomethyluridine, beta-D-galactosylqueosine, 1- methyladenosine, 1 -methylinosine, 2,2-dimethylguanosine, 3-methylcytidine, 2- methyladenosine, 2 -methyl guanosine, N6-methyladenosine, 7-methylguanosine, 5- methoxyaminomethyl-2-thiouridine, 5-methylaminomethyluridine, 5- methylcarbonylmethyluridine, 5-methyloxyuridine, 5-methyl-2-thiouridine, 2-mefhylthio-N6- isopentenyladenosine, beta-D-mannosylqueosine, uridine-5-oxyacetic acid, 2-thiocytidine, threonine derivatives and others (Burgin et al, 1996, Biochemistry, 35, 14090; Uhlman & Peyman, supra). By "modified bases" in this aspect is meant nucleoside bases other than adenine, guanine, cytosine and uracil at 1' position or their equivalents; such bases can be used at any position, for example, within the catalytic core of an enzymatic nucleic acid molecule and/or in the substrate-binding regions ofthe nucleic acid molecule.
In one embodiment, the invention features modified enzymatic nucleic acid molecules with phosphate backbone modifications comprising one or more phosphorothioate, phosphorodithioate, methylphosphonate, moφholino, amidate carbamate, carboxymethyl, acetamidate, polyamide, sulfonate, sulfonamide, sulfamate, formacetal, thioformacetal, and/or alkylsilyl, substitutions. For a review of oligonucleotide backbone modifications see Hunziker and Leumann, 1995, Nucleic Acid Analogues: Synthesis and Properties, in Modern Synthetic Methods, NCH, 331-417, and Mesmaeker et al, 1994, Novel Backbone Replacements for Oligonucleotides, in Carbohydrate Modifications in Antisense Research, ACS, 24-39. These references are hereby incoφorated by reference herein.
By "abasic" is meant sugar moieties lacking a base or having other chemical groups in place of a base at the 1' position, for example a 3 ',3 '-linked or 5 ',5 '-linked deoxyabasic ribose derivative (for more details see Wincott et al, International PCT publication No. WO 97/26270).
By "unmodified nucleoside" is meant one of the bases adenine, cytosine, guanine, thymine, uracil joined to the 1' carbon of β-D-ribo-furanose.
By "modified nucleoside" is meant any nucleotide base that contains a modification in the chemical stmcture of an unmodified nucleotide base, sugar and/or phosphate.
In connection with 2 '-modified nucleotides as described for the present invention, by
"amino" is meant 2'-NH2 or 2'-O- NH2, which can be modified or unmodified. Such modified groups are described, for example, in Eckstein et al, U.S. Patent 5,672,695 and Matulic-Adamic et al, WΟ 98/28317, respectively, which are both incoφorated by reference in their entireties.
Various modifications to nucleic acid {e.g., antisense and ribozyme) stmcture can be made to enhance the utility of these molecules. For example, such modifications can enhance shelf-life, half-life in vitro, stability, and ease of introduction of such oligonucleotides to the target site, including e.g., enhancing penetration of cellular membranes and conferring the ability to recognize and bind to targeted cells.
Use of the nucleic acid-based molecules of the invention can lead to better treatment of the disease progression by affording the possibility of combination therapies (e.g., multiple enzymatic nucleic acid molecules targeted to different genes, enzymatic nucleic acid molecules coupled with known small molecule inhibitors, or intermittent treatment with combinations of enzymatic nucleic acid molecules (including different enzymatic nucleic acid molecule motifs) and/or other chemical or biological molecules). The treatment of patients with nucleic acid molecules can also include combinations of different types of nucleic acid molecules. Therapies can be devised which include a mixture of enzymatic nucleic acid molecules (including different enzymatic nucleic acid molecule motifs), antisense and/or 2- 5 A chimera molecules to one or more targets to alleviate symptoms of a disease.
Administration of Nucleic Acid Molecules
Methods for the delivery of nucleic acid molecules are described in Akhtar et al, 1992, Trends Cell Bio., 2, 139; and Delivery Strategies for Antisense Oligonucleotide Therapeutics, ed. Akhtar, 1995 which are both incoφorated herein by reference. Sullivan et al, PCT WO 94/02595, further describes the general methods for delivery of enzymatic RNA molecules. These protocols can be utilized for the delivery of virtually any nucleic acid molecule. Nucleic acid molecules can be administered to cells by a variety of methods known to those familiar to the art, including, but not restricted to, encapsulation in liposomes, by iontophoresis, or by incoφoration into other vehicles, such as hydrogels, cyclodextrins, biodegradable nanocapsules, and bioadhesive microspheres. The nucleic acid molecules or the invention are administered via pulmonary delivery, such as by inhalation of an aerosol or spray dried formulation administered by an inhalation device or nebulizer. Alternatively, the nucleic acid/vehicle combination is locally delivered by direct injection or by use of an infusion pump. Other routes of delivery include, but are not limited to oral (tablet or pill form) and/or intrathecal delivery (Gold, 1997, Neuroscience, 76, 1153-1158). Other approaches include the use of various transport and carrier systems, for example though the use of conjugates and biodegradable polymers. For a comprehensive review on dmg delivery strategies including CNS delivery, see Ho et al, 1999, Curr. Opin. Mol. Ther., 1, 336-343 and Jain, Drug Delivery Systems: Technologies and Commercial Opportunities, Decision Resources, 1998 and Groothuis et al, 1997, J. NeuroVirol, 3, 387-400. More detailed descriptions of nucleic acid delivery and administration are provided in Sullivan et al, supra, Draper et al, PCT WO93/23569, Beigelman et al, PCT WO99/05094, and Klimuk et al, PCT WO99/04819 all of which have been incoφorated by reference herein.
Experiments have demonstrated the efficient in vivo uptake of nucleic acids by neurons. As an example of local administration of nucleic acids to nerve cells, Sommer et al, 1998, Antisense Nuc. Acid Drug Dev., 8, 75, describe a study in which a 15mer phosphorothioate antisense nucleic acid molecule to c-fos is administered to rats via microinjection into the brain. Antisense molecules labeled with tetramethylrhodamine-isothiocyanate (TRITC) or fluorescein isothiocyanate (FITC) were taken up by exclusively by neurons thirty minutes post-injection. A diffuse cytopiasmic staining and nuclear staining was observed in these cells. As an example of systemic administration of nucleic acid to nerve cells, Epa et al, 2000, Antisense Nuc. Acid Drug Dev., 10, 469, describe an in vivo mouse study in which beta-cyclodextrin-adamantane-oligonucleotide conjugates were used to target the p75 neurotrophin receptor in neuronally differentiated PC 12 cells. Following a two week course of IP administration, pronounced uptake of p75 neurotrophin receptor antisense was observed in dorsal root ganglion (DRG) cells. In addition, a marked and consistent down-regulation of p75 was observed in DRG neurons. Additional approaches to the targeting of nucleic acid to neurons are described in Broaddus et al, 1998, J. Neurosurg., 88(4), 734; Karle et al, 1997, Eur. J. Pharmocol, 340(2/3), 153; Bannai et al, 1998, Brain Research, 784(1,2), 304; Rajakumar et al, 1997, Synapse, 26(3), 199; Wu-pong et al, 1999, BioPharm, 12(1), 32; Bannai et al, 1998, Brain Res. Protoc, 3(1), 83; Simantov et al, 1996, Neuroscience, 74(1), 39. Nucleic acid molecules of the invention are therefore amenable to delivery to and uptake by cells that express NOGO and NOGO receptors for modulation of NOGO and/or NOGO receptor expression.
The delivery of nucleic acid molecules of the invention, targeting NOGO and NOGO receptors is provided by a variety of different strategies. Traditional approaches to CNS delivery that can be used include, but are not limited to, intrathecal and intracerebroventricular administration, implantation of catheters and pumps, direct injection or perfusion at the site of injury or lesion, injection into the brain arterial system, or by chemical or osmotic opening ofthe blood-brain barrier. Other approaches can include the use of various transport and carrier systems, for example though the use of conjugates and biodegradable polymers. Furthermore, gene therapy approaches, for example as described in Kaplitt et al, US 6,180,613, can be used to express nucleic acid molecules in the CNS.
The molecules of the instant invention can be used as pharmaceutical agents. Pharmaceutical agents prevent, inhibit the occurrence, or treat (alleviate a symptom to some extent, or all ofthe symptoms) of a disease state in a patient.
The negatively charged polynucleotides of the invention can be administered {e.g.,
RNA, DNA or protein) and introduced into a patient by any standard means, with or without stabilizers, buffers, and the like, to form a pharmaceutical composition. When it is desired to use a liposome delivery mechanism, standard protocols for formation of liposomes can be followed. The compositions of the present invention can also be formulated and used as tablets, capsules or elixirs for oral administration; suppositories for rectal administration; sterile solutions; suspensions for injectable administration; and the other compositions known in the art.
The present invention also includes pharmaceutically acceptable formulations of the compounds described. These formulations include salts of the above compounds, e.g., acid addition salts, for example, salts of hydrochloric, hydrobromic, acetic acid, and benzene sulfonic acid. A pharmacological composition or formulation refers to a composition or formulation in a form suitable for administration, e.g., local administration or systemic administration, into a cell or patient, including, for example, a human. Suitable forms, in part, depend upon the use or the route of entry, for example oral, transdermal, or by injection. Such forms should not prevent the composition or formulation from reaching a target cell {i.e., a cell to which the negatively charged polymer is desired to be delivered to). For example, pharmacological compositions injected into the blood stream should be soluble. Other factors are known in the art, and include considerations such as toxicity and forms which prevent the composition or formulation from exerting its effect.
By "local administration" is meant in vivo local absoφtion or accumulation of drugs in the specific tissue, organ, or compartment of the body. Administration routes that can lead to local absoφtion include, without limitations: inhalation, direct injection, or dermatological applications.
By "systemic administration" is meant in vivo systemic absoφtion or accumulation of dmgs in the blood stream followed by distribution throughout the entire body.
Administration routes which lead to systemic absoφtion include, without limitations: intravenous, subcutaneous, intraperitoneal, inhalation, oral, intrapulmonary and intramuscular. Each of these administration routes expose the desired compound, e.g., nucleic acids, to an accessible diseased tissue. The rate of entry of a dmg into the circulation has been shown to be a function of molecular weight or size. The use of a liposome or other dmg carrier comprising the compounds of the instant invention, for example PEG or phospholipids conjugates, can potentially localize the dmg, for example, in certain tissue types, such as the tissues of the reticular endothelial system (RES). A nucleic acid formulation that can facilitate the association of dmg with the surface of cells, such as, lymphocytes and macrophages is also useful. This approach can provide enhanced delivery of the dmg to target cells by taking advantage of the specificity of macrophage and lymphocyte immune recognition of abnormal cells.
Both local and systemic administration approaches can be used to administer nucleic acid molecules of the invention for the treatment of asthma or related conditions. In one embodiment, the nucleic acid molecule or formulation comprising the nucleic acid molecule is administered to a patient with an inhaler or nebulizer, providing rapid local uptake of the nucleic acid molecules into relevant pulmonary tissues. In another embodiment, the nucleic acid molecule or formulation comprising the nucleic acid molecule is administered to a patient systemically, for example by intravenous or subcutaneous injection, providing sustained uptake ofthe nucleic acid molecules into relevant bodily tissues. By pharmaceutically acceptable formulation is meant, a composition or formulation that allows for the effective distribution of the nucleic acid molecules of the instant invention in the physical location most suitable for their desired activity. Non-limiting examples of agents suitable for formulation with the nucleic acid molecules of the instant invention include: PEG conjugated nucleic acids, phospholipid conjugated nucleic acids, nucleic acids containing lipophilic moieties, phosphorothioates, P-glycoprotein inhibitors (such as Pluronic P85) which can enhance entry of dmgs into various tissues, for exaple the CNS (Jolliet-Riant and Tillement, 1999, Fundam. Clin. Pharmacol, 13, 16-26); biodegradable polymers, such as poly (DL-lactide-coglycolide) microspheres for sustained release delivery after implantation (Emerich, DF et al, 1999, Cell Transplant, 8, 47-58) Alkermes, Inc. Cambridge, MA; and loaded nanoparticles, such as those made of polybutylcyanoacrylate, which can deliver dmgs across the blood brain barrier and can alter neuronal uptake mechanisms {Prog N eur opsychopharmacol Biol Psychiatry , 23, 941-949, 1999). Other non-limiting examples of delivery strategies, including CNS delivery of the nucleic acid molecules of the instant invention include material described in Boado et al, 1998, J. Pharm. Sci., 87, 1308-1315; Tyler et al, 1999, FEBS Lett., 421, 280-284; Pardridge et al, 1995, PNAS USA., 92, 5592- 5596; Boado, 1995, Adv. Drug Delivery Rev., 15, 73-107; Aldrian-Henada et al, 1998, Nucleic Acids Res., 26, 4910-4916; and Tyler et al, 1999, PNAS USA., 96, 7053-7058. All these references are hereby incoφorated herein by reference.
The invention also features the use of the composition comprising surface-modified liposomes containing poly (ethylene glycol) lipids (PEG-modified, or long-circulating liposomes or stealth liposomes). Nucleic acid molecules of the invention can also comprise covalently attached PEG molecules of various molecular weights. These formulations offer a method for increasing the accumulation of dmgs in target tissues. This class of dmg carriers resists opsonization and elimination by the mononuclear phagocytic system (MPS or RES), thereby enabling longer blood circulation times and enhanced tissue exposure for the encapsulated dmg (Lasic et al. Chem. Rev. 1995, 95, 2601-2627; Ishiwata et al, Chem. Pharm. Bull. 1995, 43, 1005-1011). Such liposomes have been shown to accumulate selectively in tumors, presumably by extravasation and capture in the neovascularized target tissues (Lasic et al, Science 1995, 267, 1275-1276; Oku et α/., 1995, Biochim. Biophys. Acta, 1238, 86-90). The long-circulating liposomes enhance the pharmacokinetics and pharmacodynamics of DNA and RNA, particularly compared to conventional cationic liposomes which are known to accumulate in tissues of the MPS (Liu et al, J. Biol. Chem. 1995, 42, 24864-24870; Choi et al, International PCT Publication No. WO 96/10391; Ansell et al, International PCT Publication No. WO 96/10390; Holland et al, International PCT Publication No. WO 96/10392; all of which are incoφorated by reference herein). Long- circulating liposomes are also likely to protect dmgs from nuclease degradation to a greater extent compared to cationic liposomes, based on their ability to avoid accumulation in metabolically aggressive MPS tissues such as the liver and spleen. All of these references are incoφorated by reference herein.
The present invention also includes compositions prepared for storage or administration that include a pharmaceutically effective amount of the desired compounds in a pharmaceutically acceptable carrier or diluent. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A.R. Gennaro edit. 1985) hereby incoφorated by reference herein. For example, preservatives, stabilizers, dyes and flavoring agents can be provided. These include sodium benzoate, sorbic acid and esters of p- hydroxybenzoic acid. In addition, antioxidants and suspending agents can be used.
A pharmaceutically effective dose is that dose required to prevent, inhibit the occurrence, or treat (alleviate a symptom to some extent, or all of the symptoms) of a disease state. The pharmaceutically effective dose depends on the type of disease, the composition used, the route of administration, the type of mammal being treated, the physical characteristics of the specific mammal under consideration, concurrent medication, and other factors which those skilled in the medical arts will recognize. Generally, an amount between 0.1 mg/kg and 100 mg/kg body weight/day of active ingredients is administered dependent upon potency ofthe negatively charged polymer.
The nucleic acid molecules of the invention and formulations thereof can be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes percutaneous, subcutaneous, intravascular (e.g., intravenous), intramuscular, or intrathecal injection or infusion techniques and the like. In addition, there is provided a pharmaceutical formulation comprising a nucleic acid molecule of the invention and a pharmaceutically acceptable carrier. One or more nucleic acid molecules of the invention can be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants, and if desired other active ingredients. The pharmaceutical compositions containing nucleic acid molecules of the invention can be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
Compositions intended for oral use can be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more such sweetening agents, flavoring agents, coloring agents or preservative agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients can be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, com starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets can be uncoated or they can be coated by known techniques. In some cases such coatings can be prepared by known techniques to delay disintegration and absoφtion in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monosterate or glyceryl distearate can be employed.
Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropyl-methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents can be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions can also contain one or more preservatives, for example ethyl, or n-propyl p- hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
Oily suspensions can be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions can contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents and flavoring agents can be added to provide palatable oral preparations. These compositions can be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents or suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, can also be present.
Pharmaceutical compositions of the invention can also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil or a mineral oil or mixtures of these. Suitable emulsifying agents can be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions can also contain sweetening and flavoring agents.
Syrups and elixirs can be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol, glucose or sucrose. Such formulations can also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions can be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents that have been mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this puφose any bland fixed oil can be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The nucleic acid molecules of the invention can also be administered in the form of suppositories, e.g., for rectal administration ofthe dmg. These compositions can be prepared by mixing the dmg with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the dmg. Such materials include cocoa butter and polyethylene glycols.
Nucleic acid molecules of the invention can be administered parenterally in a sterile medium. The dmg, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.
Dosage levels of the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per patient per day). The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form varies depending upon the host treated and the particular mode of administration. Dosage unit forms generally contain between from about 1 mg to about 500 mg of an active ingredient.
It is understood that the specific dose level for any particular patient depends upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, dmg combination and the severity ofthe particular disease undergoing therapy.
For administration to non-human animals, the composition can also be added to the animal feed or drinking water. It can be convenient to formulate the animal feed and drinking water compositions so that the animal takes in a therapeutically appropriate quantity of the composition along with its diet. It can also be convenient to present the composition as a premix for addition to the feed or drinking water.
The nucleic acid molecules of the present invention can also be administered to a patient in combination with other therapeutic compounds to increase the overall therapeutic effect. The use of multiple compounds to treat an indication can increase the beneficial effects while reducing the presence of side effects.
Alternatively, certain of the nucleic acid molecules of the instant invention can be expressed within cells from eukaryotic promoters {e.g., Izant and Weintraub, 1985, Science, 229, 345; McGarry and Lindquist, 1986, Proc Natl. Acad. Sci., USA 83, 399; Scanlon et al, 1991, Proc. Natl. Acad. Sci. USA, 88, 10591-5; Kashani-Sabet et al, 1992, Antisense Res. Dev., 2, 3-15; Dropulic et al, 1992, J. Virol, 66, 1432-41; Weerasinghe et al, 1991, J. Virol, 65, 5531-4; Ojwang et al, 1992, Proc. Natl. Acad. Sci. USA, 89, 10802-6; Chen et al, 1992, Nucleic Acids Res., 20, 4581-9; Sarver et al, 1990 Science, 247, 1222-1225; Thompson et al, 1995, Nucleic Acids Res., 23, 2259; Good et al, 1997, Gene Therapy, 4, 45; all of these references are hereby incoφorated in their totalities by reference herein). Those skilled in the art realize that any nucleic acid can be expressed in eukaryotic cells from the appropriate DNA/RNA vector. The activity of such nucleic acids can be augmented by their release from the primary transcript by a enzymatic nucleic acid (Draper et al, PCT WO 93/23569, and Sullivan et al, PCT WO 94/02595; Ohkawa et al, 1992, Nucleic Acids Symp. Ser., 27, 15-6; Taira et al, 1991, Nucleic Acids Res., 19, 5125-30; Ventura et al, 1993, Nucleic Acids Res., 21, 3249-55; Chowrira et al, 1994, J. Biol. Chem., 269, 25856; all of these references are hereby incoφorated in their totalities by reference herein). Gene therapy approaches specific to the CNS are described by Blesch et al, 2000, Drug News Perspect, 13, 269-280; Peterson et al, 2000, Cent. Nerv. Syst. Dis., 485-508; Peel and Klein, 2000, J. Neurosci. Methods, 98, 95-104; Hagihara et al, 2000, Gene Ther., 1, 759-763; and Herrlinger et al, 2000, Methods Mol. Med., 35, 287-312. AAN-mediated delivery of nucleic acid to cells ofthe nervous system is further described by Kaplitt et al, US 6,180,613.
In another aspect of the invention, RΝA molecules of the present invention can be expressed from transcription units (see for example Couture et al, 1996, TIG, 12, 510) inserted into DΝA or RΝA vectors. The recombinant vectors can be DΝA plasmids or viral vectors. Ribozyme expressing viral vectors can be constmcted based on, but not limited to, adeno-associated vims, retrovims, adenovims, or alphavims. The recombinant vectors capable of expressing the nucleic acid molecules can be delivered as described above, and persist in target cells. Alternatively, viral vectors can be used that provide for transient expression of nucleic acid molecules. Such vectors can be repeatedly administered as necessary. Once expressed, the nucleic acid molecule binds to the target mRΝA. Delivery of nucleic acid molecule expressing vectors can be systemic, such as by intravenous or intramuscular administration, by administration to target cells ex-planted from the patient followed by reintroduction into the patient, or by any other means that would allow for introduction into the desired target cell (for a review see Couture et al, 1996, TIG., 12, 510).
In one aspect the invention features an expression vector comprising a nucleic acid sequence encoding at least one of the nucleic acid molecules of the instant invention is disclosed. The nucleic acid sequence encoding the nucleic acid molecule of the instant invention is operably linked in a manner that allows expression of that nucleic acid molecule.
In another aspect the invention features an expression vector comprising: a) a transcription initiation region {e.g., eukaryotic pol I, II or m initiation region); b) a transcription termination region {e.g., eukaryotic pol I, II or m termination region); c) a nucleic acid sequence encoding at least one of the nucleic acid catalyst of the instant invention; and wherein said sequence is operably linked to said initiation region and said termination region, in a manner that allows expression and/or delivery of said nucleic acid molecule. The vector can optionally include an open reading frame (ORF) for a protein operably linked on the 5' side or the 3 '-side ofthe sequence encoding the nucleic acid catalyst ofthe invention; and/or an intron (intervening sequences).
Transcription of the nucleic acid molecule sequences are driven from a promoter for eukaryotic RΝA polymerase I (pol I), RΝA polymerase II (pol U), or RΝA polymerase UI (pol UI). Transcripts from pol π or pol UI promoters are expressed at high levels in all cells; the levels of a given pol π promoter in a given cell type depends on the nature of the gene regulatory sequences (enhancers, silencers, etc.) present nearby. Prokaryotic RΝA polymerase promoters are also used, providing that the prokaryotic RΝA polymerase enzyme is expressed in the appropriate cells (Elroy-Stein and Moss, 1990, Proc. Natl. Acad. Sci. US A, 87, 6743-7; Gao and Huang 1993, Nucleic Acids Res., 21, 2867-72; Lieber et al, 1993, Methods Enzymol, 217, 47-66; Zhou et al, 1990, Mol. Cell. Biol, 10, 4529-37). All of these references are incoφorated by reference herein. Several investigators have demonstrated that nucleic acid molecules, such as ribozymes expressed from such promoters can function in mammalian cells (e.g. Kashani-Sabet et al, 1992, Antisense Res. Dev., 2, 3- 15; Ojwang et al, 1992, Proc. Natl. Acad. Sci. U S A, 89, 10802-6; Chen et al, 1992, Nucleic Acids Res., 20, 4581-9; Yu et al, 1993, Proc. Natl. Acad. Sci. U S A, 90, 6340-4; L'Huillier et al, 1992, EMBO J, 11, 4411-8; Lisziewicz et al, 1993, Proc. Natl. Acad. Sci. U S. A, 90, 8000-4; Thompson et al, 1995, Nucleic Acids Res., 23, 2259; Sullenger & Cech, 1993, Science, 262, 1566). More specifically, transcription units such as the ones derived from genes encoding U6 small nuclear (snRNA), transfer RNA (tRNA) and adenovims VA RNA are useful in generating high concentrations of desired RNA molecules such as ribozymes in cells (Thompson et al, supra; Couture and Stinchcomb, 1996, supra; Noonberg et al, 1994, Nucleic Acid Res., 22, 2830; Noonberg et al, US Patent No. 5,624,803; Good et al, 1997, Gene Ther., 4, 45; Beigelman et al, International PCT Publication No. WO 96/18736; all of these publications are incoφorated by reference herein). The above ribozyme transcription units can be incoφorated into a variety of vectors for introduction into mammalian cells, including but not restricted to, plasmid DNA vectors, viral DNA vectors (such as adenovims or adeno-associated vims vectors), or viral RNA vectors (such as retroviral or alphavims vectors) (for a review see Couture and Stinchcomb, 7996, supra).
In another aspect the invention features an expression vector comprising a nucleic acid sequence encoding at least one of the nucleic acid molecules of the invention, in a manner that allows expression of that nucleic acid molecule. The expression vector comprises in one embodiment; a) a transcription initiation region; b) a transcription termination region; c) a nucleic acid sequence encoding at least one said nucleic acid molecule; and wherein said sequence is operably linked to said initiation region and said termination region, in a manner that allows expression and/or delivery of said nucleic acid molecule.
In another embodiment the expression vector comprises: a) a transcription initiation region; b) a transcription termination region; c) an open reading frame; d) a nucleic acid sequence encoding at least one said nucleic acid molecule, wherein said sequence is operably linked to the 3'-end of said open reading frame; and wherein said sequence is operably linked to said initiation region, said open reading frame and said termination region, in a manner that allows expression and/or delivery of said nucleic acid molecule. In yet another embodiment the expression vector comprises: a) a transcription initiation region; b) a transcription termination region; c) an intron; d) a nucleic acid sequence encoding at least one said nucleic acid molecule; and wherein said sequence is operably linked to said initiation region, said intron and said termination region, in a manner which allows expression and/or delivery of said nucleic acid molecule.
In another embodiment, the expression vector comprises: a) a transcription initiation region; b) a transcription termination region; c) an intron; d) an open reading frame; e) a nucleic acid sequence encoding at least one said nucleic acid molecule, wherein said sequence is operably linked to the 3'-end of said open reading frame; and wherein said sequence is operably linked to said initiation region, said intron, said open reading frame and said termination region, in a manner which allows expression and/or delivery of said nucleic acid molecule.
Examples.
The following are non-limiting examples showing the selection, isolation, synthesis and activity of nucleic acids ofthe instant invention.
Example 1 : Nucleic acid molecules targeting PTGDS. ADORAl and PTGDR RNA
The invention features novel nucleic acid-based molecules, for example, enzymatic nucleic acid molecules, allozymes, antisense nucleic acids, 2-5A antisense chimeras, triplex forming oligonucleotides, decoy RNA, dsRNA, siRNA, aptamers, and antisense nucleic acids containing RNA cleaving chemical groups, and methods to modulate gene expression, for example, genes encoding prostaglandin D2 receptor (PTGDR), prostaglandin D2 synthetase (PTGDS), and adenosine receptors (AR) such as adenosine receptor Al, A2a, A2b, and A3. ta particular, the instant invention features nucleic-acid based molecules and methods to modulate the expression of PTGDR, PTGDS, and adenosine Al receptor (ADORAl).
In one embodiment, the invention features one or more nucleic acid-based molecules and methods that independently or in combination modulate the expression of gene(s) encoding prostaglandin D2 receptors (PTGDR), prostaglandin D2 synthetase (PTGDS) and adenosine receptors such as ADORAl. Specifically, the present invention features nucleic acid molecules that modulate the expression of prostaglandin D2 receptor (PTGDR) gene, for example Genbank Accession Nos. U31332 and U31099, prostaglandin D2 synthetase (PTGDS) gene, for example Genbank Accession No. NM_000954, and Adenosine Al receptor (ADORAl), for example Genbank Accession No. NM_000674.
In another embodiment, the invention features an enzymatic nucleic acid molecule comprising a sequence selected from the group consisting of SEQ ID NOs: 11666-13262. ta yet another embodiment, the invention features an enzymatic nucleic acid molecule comprising at least one binding arm wherein one or more of said binding arms comprises a sequence complementary to a sequence selected from the group consisting of SEQ ED NOs: 4415-5483.
In one embodiment, the invention features an antisense nucleic acid molecule comprising a sequence complementary to a sequence selected from the group consisting of SEQ ID NOs: 4415-5483.
In another embodiment, an enzymatic nucleic acid molecule, antisense nucleic acid molecule, 2-5A antisense chimera, triplex forming oligonucleotide, decoy RNA, dsRNA, siRNA, aptamer, or antisense nucleic acids containing RNA cleaving chemical groups of the invention is adapted to treat asthma.
ta one embodiment, an enzymatic nucleic acid molecule of the invention has an endonuclease activity to cleave RNA encoded by a PTGDS and/or PTGDR gene.
In another embodiment, an enzymatic nucleic acid molecule of the invention is in a hammerhead, taozyme, Zinzyme, DNAzyme, Amberzyme, or G-cleaver configuration.
In another embodiment, an enzymatic nucleic acid molecule of the invention having a hammerhead configuration comprises a sequence complementary to a sequence having SEQ
ID NOS: 4415-4641. ta yet another embodiment, an enzymatic nucleic acid molecule of invention having a hammerhead configuration comprises a sequence having SEQ ID NOs:
11666-11892.
ta another embodiment, an enzymatic nucleic acid molecule of the invention having an taozyme configuration comprises a sequence complementary to a sequence having SEQ
ID NOS: 4642-5017. ta yet another embodiment, an enzymatic nucleic acid molecule of invention having an taozyme configuration comprises a sequence having SEQ ID NOs:
11893-12268.
In another embodiment, an enzymatic nucleic acid molecule of the invention having a Zinzyme configuration comprises a sequence complementary to a sequence having SEQ ID
NOs: 5018-5248. ta yet another embodiment, an enzymatic nucleic acid molecule of invention having a Zinzyme configuration comprises a sequence having SEQ DD NOs: 12269-
12499.
In another embodiment, an enzymatic nucleic acid molecule of the invention having a DNAzyme configuration comprises a sequence complementary to a sequence having SEQ ED
NOs: 4415-5294. In yet another embodiment, an enzymatic nucleic acid molecule of invention having a DNAzyme configuration comprises a sequence having SEQ ED NOs:
12500-12842. In another embodiment, an enzymatic nucleic acid molecule of the invention having an Amberzyme configuration comprises a sequence complementary to a sequence having
SEQ ED NOs: 5018-5248, and 5295-5483. ta yet another embodiment, an enzymatic nucleic acid molecule of invention having an Amberzyme configuration comprises a sequence having SEQ ED NOs: 12843-13262.
In one embodiment, an enzymatic nucleic acid molecule of the invention comprises between 8 and 100 bases complementary to the RNA of PTGDS, ADORAl and/or PTGDR gene, ta another embodiment, an enzymatic nucleic acid molecule ofthe invention comprises between 14 and 24 bases complementary to a RNA molecule of a PTGDS or PTGDR gene.
ta one embodiment, an enzymatic nucleic acid molecule, antisense nucleic acid molecule, 2-5A antisense chimera, triplex forming oligonucleotide, decoy RNA, dsRNA, siRNA, aptamer, or antisense nucleic acids containing RNA cleaving chemical groups of the invention is chemically synthesized.
ta another embodiment, an enzymatic nucleic acid molecule, antisense nucleic acid molecule, 2-5 A antisense chimera, triplex forming oligonucleotide, decoy RNA, dsRNA, siRNA, aptamer, or antisense nucleic acids containing RNA cleaving chemical groups of the invention comprises at least one 2'-sugar modification.
ta another embodiment, an enzymatic nucleic acid molecule, antisense nucleic acid molecule, 2-5A antisense chimera, triplex forming oligonucleotide, decoy RNA, dsRNA, siRNA, aptamer, or antisense nucleic acids containing RNA cleaving chemical groups of the invention comprises at least one nucleic acid base modification.
ta another embodiment, an enzymatic nucleic acid molecule, antisense nucleic acid molecule, 2-5A antisense chimera, triplex forming oligonucleotide, decoy RNA, dsRNA, siRNA, aptamer, or antisense nucleic acids containing RNA cleaving chemical groups of the invention comprises at least one phosphate backbone modification.
ta one embodiment, the invention features a mammalian cell, for example a human cell, including the enzymatic nucleic acid molecule ofthe invention.
ta another embodiment, the invention features a method of reducing PTGDS, ADORAl and/or PTGDR expression or activity in a cell, comprising contacting the cell with an enzymatic nucleic acid molecule of the invention, under conditions suitable for the reduction.
ta another embodiment, the invention features a method of reducing PTGDS, ADORAl and/or PTGDR expression or activity in a cell, comprising the step of contacting the cell with an antisense nucleic acid molecule of the invention under conditions suitable for the reduction.
ta yet another embodiment, the invention features a method of treatment of a patient having a condition associated with the level of PTGDS, ADORAl and/or PTGDR, comprising contacting cells of the patient with an enzymatic nucleic acid molecule of the invention, under conditions suitable for the treatment.
ta one embodiment, the invention features a method of treatment of a patient having a condition associated with the level of PTGDS, ADORAl and/or PTGDR, comprising contacting cells of the patient with an antisense nucleic acid molecule of the invention, under conditions suitable for the treatment.
ta another embodiment, a method of treatment of a patient having a condition associated with the level of PTGDS, ADORAl and/or PTGDR is featured, wherein the method further comprises the use of one or more dmg therapies under conditions suitable for the treatment.
For example, in one embodiment, the invention features a method for treatment of asthma, allergic rhinitis, or atopic dermatitis under conditions suitable for the treatment.
ta another embodiment, the invention features a method of cleaving a RNA molecule of PTGDS, ADORAl and/or PTGDR gene comprising contacting an enzymatic nucleic acid molecule ofthe invention with a RNA molecule of a PTGDS, ADORAl and/or PTGDR gene under conditions suitable for the cleavage, for example, wherein the cleavage is carried out in the presence of a divalent cation, such as Mg2+.
ta one embodiment, an enzymatic nucleic acid molecule of the invention comprises a cap stmcture, for example a 3',3'-linked or 5',5'-linked deoxyabasic ribose derivative, wherein the cap stmcture is at the 5 '-end, or 3 '-end, or both the 5 '-end and the 3 '-end of the enzymatic nucleic acid molecule.
ta another embodiment, an antisense nucleic acid molecule of the invention comprises a cap stmcture, for example a 3',3'-linked or 5',5'-linked deoxyabasic ribose derivative, wherein the cap stmcture is at the 5 '-end, or 3 '-end, or both the 5 '-end and the 3 '-end of the antisense nucleic acid molecule.
ta one embodiment, the invention features an expression vector comprising a nucleic acid sequence encoding at least one enzymatic nucleic acid molecule of the invention, in a manner which allows expression ofthe nucleic acid molecule. In another embodiment, the invention features a mammalian cell, for example, a human cell, including an expression vector ofthe invention.
ta yet another embodiment, the expression vector of the invention further comprises a sequence for an antisense nucleic acid molecule complementary to a RNA molecule of a PTGDS, ADORAl and/or PTGDR gene.
In one embodiment, an expression vector of the invention comprises a nucleic acid sequence encoding two or more enzymatic nucleic acid molecules, which can be the same or different.
ta another embodiment, the invention features a method for treatment of asthma, allergic rhinitis, or atopic dermatitis, comprising administering to a patient an enzymatic nucleic acid molecule, antisense nucleic acid molecule, 2-5A antisense chimera, triplex forming oligonucleotide, decoy RNA, dsRNA, siRNA, aptamer, or antisense nucleic acid containing RNA cleaving chemical groups of the invention, under conditions suitable for the treatment, including administering to the patient one or more other therapies, for example, inhalant anti-inflammatories, bronchodilators, adenosine inhibitors and adenosine Al receptor inhibitors.
ta one embodiment, the method of treatment features an enzymatic nucleic acid molecule or antisense nucleic acid molecule of the invention comprises at least five ribose residues, at least ten 2'-O-methyl modifications, and a 3'- end modification, such as a 3 '-3' inverted abasic moiety, ta another embodiment, an enzymatic nucleic acid molecule or antisense nucleic acid molecule of the invention further comprises phosphorothioate linkages on at least three ofthe 5' terminal nucleotides.
ta another embodiment, the invention features a method of administering to a mammal, for example a human, an enzymatic nucleic acid molecule, antisense nucleic acid molecule, 2- 5 A antisense chimera, triplex forming oligonucleotide, decoy RNA, dsRNA, siRNA, aptamer, or antisense nucleic acid containing RNA cleaving chemical groups of the invention, comprising contacting the mammal with the nucleic acid molecule under conditions suitable for the administration, for example, in the presence of a delivery reagent such as a lipid, cationic lipid, phospholipid, or liposome.
ta yet another embodiment, the invention features a method of administering to a mammal an enzymatic nucleic acid molecule, antisense nucleic acid molecule, 2-5A antisense chimera, triplex forming oligonucleotide, decoy RNA, dsRNA, siRNA, aptamer, or antisense nucleic acid containing RNA cleaving chemical groups of the invention in conjunction with a therapeutic agent, comprising contacting the mammal, for example a human, with the nucleic acid molecule and the therapeutic agent under conditions suitable for the administration. In one embodiment, the invention features the use of an enzymatic nucleic acid molecule, which can be in a hammerhead, NCH, G-cleaver, Amberzyme, Zinzyme, and/or DNAzyme motif, to down-regulate the expression of a PTGDS, an ADORAl and/or a PTGDR gene.
The enzymatic nucleic acid molecule that cleave the specified sites in PTGDS,
ADORAl and PTGDR-specific RNAs represent a novel therapeutic approach to treat a variety of allergic diseases or conditions, including but not limited to asthma, allergic rhinitis, atopic dermatitis, and/or other allergic or inflammatory diseases and conditions which respond to the modulation of PTGDS, ADORAl and or PTGDR expression.
ta one embodiment, a nucleic acid molecule that modulates, for example, down- regulates, PTGDS replication or expression comprises between 8 and 100 bases complementary to a RNA molecule of PTGDS. ta another embodiment, a nucleic acid molecule that modulates PTGDS replication or expression comprises between 14 and 24 bases complementary to a RNA molecule of PTGDS.
ta another embodiment, a nucleic acid molecule that modulates, for example, down- regulates, PTGDR replication or expression comprises between 8 and 100 bases complementary to a RNA molecule of PTGDR. In another embodiment, a nucleic acid molecule that modulates PTGDR replication or expression comprises between 14 and 24 bases complementary to a RNA molecule of PTGDR.
In another embodiment, a nucleic acid molecule that modulates, for example, down- regulates, ADORAl replication or expression comprises between 8 and 100 bases complementary to a RNA molecule of ADORAl. ta another embodiment, a nucleic acid molecule that modulates ADORAl replication or expression comprises between 14 and 24 bases complementary to a RNA molecule of ADORAl.
The invention provides a method for producing a class of nucleic acid-based gene modulating agents that exhibit a high degree of specificity for the RNA of a desired target. For example, the enzymatic nucleic acid molecule is can be targeted to a highly conserved sequence region of target RNAs encoding PTGDS, ADORAl and/or PTGDR (e.g., PTGDS, ADORAl and/or PTGDR genes) such that specific treatment of a disease or condition can be provided with either one or several nucleic acid molecules of the invention. Such nucleic acid molecules can be delivered exogenously to specific tissue or cellular targets as required. Alternatively, the nucleic acid molecules {e.g., ribozymes and antisense) can be expressed from DNA and or RNA vectors that are delivered to specific cells.
Nucleic acid-based inhibitors of PTGDS, ADORAl and PTGDR expression are useful for the prevention and/or treatment of allergic diseases or conditions, including but not limited to asthma, allergic rhinitis, atopic dermatitis, and any other diseases or conditions that are related to or will respond to the levels of PTGDS, ADORAl and/or PTGDR in a cell or tissue, alone or in combination with other therapies. The reduction of PTGDS, ADORAl and/or PTGDR expression (specifically PTGDS, ADORAl and or PTGDR gene RNA levels) and thus reduction in the level of the respective protein relieves, to some extent, the symptoms ofthe disease or condition.
The nucleic acid molecules of the instant invention, individually, or in combination or in conjunction with other dmgs, can be used to treat diseases or conditions discussed above. For example, to treat a disease or condition associated with the levels of PTGDS, ADORAl and/or PTGDR, the patient can be treated, or other appropriate cells can be treated, as is evident to those skilled in the art, individually or in combination with one or more dmgs under conditions suitable for the treatment.
In a further embodiment, the described molecules, such as antisense or enzymatic nucleic acid molecules, can be used in combination with other known treatments to treat conditions or diseases discussed above. For example, the described molecules can be used in combination with one or more known therapeutic agents to treat allergic diseases or conditions, including but not limited to asthma, allergic rhinitis, atopic dermatitis, and/or other allergic or inflammatory diseases and conditions which respond to the modulation of PTGDS, ADORAl and/or PTGDR expression.
In another embodiment, the invention features nucleic acid-based inhibitors {e.g., enzymatic nucleic acid molecules (e.g., ribozymes), antisense nucleic acids, 2-5A antisense chimeras, triplex DNA, antisense nucleic acids containing RNA cleaving chemical groups) and methods for their use to down regulate or inhibit the expression of genes {e.g., PTGDS, ADORAl and/or PTGDR) capable of progression and/or maintenance allergic diseases or conditions, including but not limited to asthma, allergic rhinitis, atopic dermatitis, and/or other allergic or inflammatory diseases and conditions which respond to the modulation of PTGDS, ADORAl and/or PTGDR expression.
Identification of Potential Target Sites in Human PTGDS, ADORAl and PTGDR RNA
The sequence of human PTGDS, ADORAl and PTGDR genes are screened for accessible sites using a computer-folding algorithm. Regions of the RNA that do not form secondary folding stmctures and contained potential enzymatic nucleic acid molecule and/or antisense binding/cleavage sites are identified. The sequences of PTGDR binding/cleavage sites are shown in Tables XIX-XXIII. Selection of Enzymatic Nucleic Acid Cleavage Sites in Human PTGDS, ADORAl and PTGDR RNA
Enzymatic nucleic acid molecule target sites are chosen by analyzing sequences of Human PTGDS (Genbank accession No: NM 000954), ADORAl (Genbank accession No: NM_000674) and PTGDR gene (Genbank accession Nos: U31332 and U31099) and prioritizing the sites on the basis of folding. Enzymatic nucleic acid molecules are designed that can bind each target and are individually analyzed by computer folding (Christoffersen et al, 1994 J. Mol. Struc Theochem, 311, 273; Jaeger et al, 1989, Proc. Natl. Acad. Sci. USA, 86, 7706) to assess whether the enzymatic nucleic acid molecule sequences fold into the appropriate secondary stmcture. Those enzymatic nucleic acid molecules with unfavorable intramolecular interactions between the binding arms and the catalytic core are eliminated from consideration. As noted below, varying binding arm lengths can be chosen to optimize activity. Generally, at least 4 bases on each arm are able to bind to, or otherwise interact with, the target RNA.
Chemical Synthesis and Purification of Ribozymes and Antisense for Efficient Cleavage and/or blocking of PTGDS, ADORAl and PTGDR RNA
Enzymatic nucleic acid molecules and antisense constmcts are designed to anneal to various sites in the RNA message. The binding arms ofthe enzymatic nucleic acid molecules are complementary to the target site sequences described above, while the antisense constmcts are fully complementary to the target site sequences described above. The enzymatic nucleic acid molecules and antisense constmcts were chemically synthesized. The method of synthesis used followed the procedure for normal RNA synthesis as described above and in Usman et al, (1987 J. Am. Chem. Soc, 109, 7845), Scaringe et al, (1990 Nucleic Acids Res., 18, 5433) and Wincott et al, supra, and made use of common nucleic acid protecting and coupling groups, such as dimethoxytrityl at the 5'-end, and phosphoramidites at the 3'-end. The average stepwise coupling yields were typically >98%.
Enzymatic nucleic acid molecules and antisense constmcts are also synthesized from DNA templates using bacteriophage T7 RNA polymerase (Milligan and Uhlenbeck, 1989, Methods Enzymol. 180, 51). Enzymatic nucleic acid molecules and antisense constmcts are purified by gel electrophoresis using general methods or are purified by high pressure liquid chromatography (HPLC; See Wincott et al, supra; the totality of which is hereby incoφorated herein by reference) and are resuspended in water. The sequences of the chemically synthesized enzymatic nucleic acid molecules used in this study are shown below in Tables XIX-XXIII. The sequences of the chemically synthesized antisense constmcts used in this study are complementary sequences to the Substrate sequences shown below as in Tables XIX-XXIII. Enzymatic nucleic acid molecule Cleavage of PTGDS, ADORAl and PTGDR RNA Target in vitro
Enzymatic nucleic acid molecules targeted to the human PTGDS, ADORAl and
PTGDR RNA are designed and synthesized as described above. These enzymatic nucleic acid molecules can be tested for cleavage activity in vitro, for example, using the following procedure. The target sequences and the nucleotide location within the PTGDR RNA are given in Tables XIX-XXIII.
Cleavage Reactions: Full-length or partially full-length, internally-labeled target RNA for enzymatic nucleic acid molecule cleavage assay is prepared by in vitro transcription in the presence of [a-32p] CTP, passed over a G 50 Sephadex column by spin chromatography and
32 used as substrate RNA without further purification. Alternately, substrates are 5'- P-end labeled using T4 polynucleotide kinase enzyme. Assays are performed by pre-warming a 2X concentration of purified enzymatic nucleic acid molecule in enzymatic nucleic acid molecule cleavage buffer (50 mM Tris-HCl, pH 7.5 at 37°C, 10 mM MgCl2) and the cleavage reaction was initiated by adding the 2X enzymatic nucleic acid molecule mix to an equal volume of substrate RNA (maximum of 1-5 nM) that was also pre-warmed in cleavage buffer. As an o initial screen, assays are carried out for 1 hour at 37 C using a final concentration of either 40 nM or 1 mM enzymatic nucleic acid molecule, i.e., enzymatic nucleic acid molecule excess.
The reaction is quenched by the addition of an equal volume of 95% formamide, 20 mM EDTA, 0.05%) bromophenol blue and 0.05%> xylene cyanol after which the sample is heated o to 95 C for 2 minutes, quick chilled and loaded onto a denaturing polyacrylamide gel. Substrate RNA and the specific RNA cleavage products generated by enzymatic nucleic acid molecule cleavage are visualized on an autoradiograph of the gel. The percentage of cleavage is determined by Phosphor Imager® quantitation of bands representing the intact substrate and the cleavage products.
In vivo models used to evaluate the down-regulation of PTGDS, ADORAl and PTGDR gene expression
Animal Models
Evaluating the efficacy of anti -PTGDS, ADORA-1 and/or PTGDR agents in animal models is an important prerequisite to human clinical trials. Matsuoka et al, 2000, Science, 287, 2012-2016, describe a useful asthma animal model having generating mice deficient in the PTGDR receptor. Sensitization and aerosol challenge of homozygous (PTGDR-/-) mice with ovalbumin was shown to induce increases in the semm concentration of immunoglobin E (IgE), an allergic mediator that activates mast cells, similar to wild-type mice subjected to the same conditions. The concentration of TH2 cytokines and the degree of lymphocyte lung infiltration in the OVA challenged PTGDR -/- mice was shown to be greatly reduced compared to wild type mice. In addition, the PTGDR -/- mice showed only marginal eosinophil infiltration and failed to develop airway hyperreactivity. Similarly, this model can be used to evaluate mice that are treated with nucleic acid molecules of the invention and can furthermore be used as a positive control in determining the response of mice treated with nucleic acid molecules of the invention by using such factors as airway obstruction, lung capacity, and bronchiolar alveolar lavage (BAL) fluid in the evaluation.
Cell Culture
Two human cell lines, NPE cells and NCB-20 cells are known to express PTGDR. Cloned human PTGDR has been expressed in CHO and COS7 cells and used in various studies. These PTGDR expressing lung cell lines can be used in cell culture assays to evaluate nucleic acid molecules of the invention. A primary endpoint in these experiments would be the RT-PCR analysis of PTGDR mRNA expression in PTGDR expressing cells, ta addition, ligand binding assays can be developed where binding of PTGDS can be evaluated in response to treatment with nucleic acid molecules ofthe invention.
Indications
The present body of knowledge in PTGDS, ADORAl and PTGDR research indicates the need for methods to assay PTGDS, ADORAl and PTGDR activity and for compounds that can regulate PTGDS, ADORAl and PTGDR expression for research, diagnostic, and therapeutic use. As described herein, the nucleic acid molecules of the present invention can be used in assays to diagnose disease state related of PTGDS, ADORAl and/or PTGDR levels. In addition, the nucleic acid molecules can be used to treat disease state related to PTGDS, ADORAl and or PTGDR levels.
Particular degenerative and disease states that can be associated with PTGDS, ADORAl and PTGDR levels include, but are not limited to allergic diseases and conditions, including but not limited to asthma, allergic rhinitis, atopic dermatitis, and any other diseases or conditions that are related to or will respond to the levels of PTGDS, ADORAl and or
PTGDR in a cell or tissue, alone or in combination with other therapies.
The use of anti-inflammatories, bronchodilators, adenosine inhibitors and adenosine Al receptor inhibitors are examples of other treatments or therapies can be combined with the nucleic acid molecules ofthe invention. Those skilled in the art will recognize that other drug compounds and therapies can be similarly be readily combined with the nucleic acid molecules of the instant invention (e.g. enzymatic nucleic acid molecules and antisense molecules) are hence within the scope ofthe instant invention. Diagnostic uses
The nucleic acid molecules of this invention {e.g., enzymatic nucleic acid molecules) can be used as diagnostic tools to examine genetic drift and mutations within diseased cells or to detect the presence of PTGDS, ADORAl and/or PTGDR RNA in a cell. The close relationship between enzymatic nucleic acid molecule activity and the stmcture of the target RNA allows the detection of mutations in any region of the molecule that alters the base- pairing and three-dimensional stmcture of the target RNA. By using multiple enzymatic nucleic acid molecules described in this invention, one can map nucleotide changes which are important to RNA stmcture and function in vitro, as well as in cells and tissues. Cleavage of target RNAs with enzymatic nucleic acid molecules can be used to inhibit gene expression and define the role (essentially) of specified gene products in the progression of disease. In this manner, other genetic targets can be defined as important mediators ofthe disease. These experiments can lead to better treatment ofthe disease progression by affording the possibility of combinational therapies {e.g., multiple enzymatic nucleic acid molecules targeted to different genes, enzymatic nucleic acid molecules coupled with known small molecule inhibitors, or intermittent treatment with combinations of enzymatic nucleic acid molecules and/or other chemical or biological molecules). Other in vitro uses of enzymatic nucleic acid molecules of this invention are well known in the art, and include detection ofthe presence of mRNAs associated with PTGDS, ADORAl or PTGDR-related condition. Such RNA is detected by determining the presence of a cleavage product after treatment with an enzymatic nucleic acid molecule using standard methodology.
In a specific example, enzymatic nucleic acid molecules which cleave only wild-type or mutant forms of the target RNA are used for the assay. The first enzymatic nucleic acid molecule is used to identify wild-type RNA present in the sample and the second enzymatic nucleic acid molecule is used to identify mutant RNA in the sample. As reaction controls, synthetic substrates of both wild-type and mutant RNA are cleaved by both enzymatic nucleic acid molecules to demonstrate the relative enzymatic nucleic acid molecule efficiencies in the reactions and the absence of cleavage of the "non-targeted" RNA species. The cleavage products from the synthetic substrates also serve to generate size markers for the analysis of wild-type and mutant RNAs in the sample population. Thus each analysis requires two enzymatic nucleic acid molecules, two substrates and one unknown sample which is combined into six reactions. The presence of cleavage products is determined using an RNAse protection assay so that full-length and cleavage fragments of each RNA can be analyzed in one lane of a polyacrylamide gel. It is not absolutely required to quantify the results to gain insight into the expression of mutant RNAs and putative risk of the desired phenotypic changes in target cells. The expression of mRNA whose protein product is implicated in the development of the phenotype {i.e., PTGDS/PTGDR) is adequate to establish risk. If probes of comparable specific activity are used for both transcripts, then a qualitative comparison of RNA levels will be adequate and will decrease the cost ofthe initial diagnosis. Higher mutant form to wild-type ratios are correlated with higher risk whether RNA levels are compared qualitatively or quantitatively. The use of enzymatic nucleic acid molecules in diagnostic applications contemplated by the instant invention is described, for example, in George et al, US Patent Nos. 5,834,186 and 5,741,679, Shih et al, US Patent No. 5,589,332, Nathan et al, US Patent No 5,871,914, Nathan and Ellington, International PCT publication No. WO 00/24931, Breaker et al, International PCT Publication Nos. WO 00/26226 and 98/27104, and Sullenger et al, International PCT publication No. WO 99/29842.
Example 2: Nucleic acid inhibition of NOGO and NOGO receptor target RNA
The invention features novel nucleic acid-based molecules [e.g., enzymatic nucleic acid molecules (ribozymes), antisense nucleic acids, 2-5A antisense chimeras, triplex DNA, decoy RNA, aptamers, siRNA, antisense nucleic acids containing RNA cleaving chemical groups] and methods to modulate gene expression, for example, genes encoding certain myelin proteins that inhibit or are involved in the inhibition of neurite growth, including axonal regeneration in the CNS. In particular, the instant invention features nucleic-acid based techniques to inhibit the expression of NOGO-A (Accession No. AJ251383), NOGO-B (Accession No. AJ251384), and/or NOGO-C (Accession No. AJ251385), NOGO-66 receptor (Accession No AF283463, Fournier et al, 2001, Nature, 409, 341-346), NI-35, NI-220, and/or NI-250, myelin-associated glycoprotein (Genbank Accession No M29273), tenascin-R (Genbank Accession No X98085), and NG-2 (Genbank Accession No X61945).
ta a preferred embodiment, the invention features the use of one or more of the nucleic acid-based techniques independently or in combination to inhibit the expression or function of the gene(s) encoding NOGO-A, NOGO-B, NOGO-C, NI-35, NI-220, NI-250, myelin- associated glycoprotein, tenascin-R, NG-2 and/or their corresponding receptors. Specifically, the invention features the use of nucleic acid-based techniques to specifically inhibit the expression of NOGO gene (Genbank Accession No. AB020693) and NOGO-66 receptor (Genbank Accession No. AF283463).
The nucleic acid molecules that interact with NOGO and NOGO receptor-specific
RNAs represent a novel therapeutic approach to treat a variety of pathologic indications, including but not limited to CNS injury and cerebrovascular accident (CVA, stroke), Alzheimer's disease, dementia, multiple sclerosis (MS), chemotherapy-induced neuropathy, amyotrophic lateral sclerosis (ALS), Parkinson's disease, ataxia, Huntington's disease, Creutzfeldt- Jakob disease, muscular dystrophy, and/or other neurodegenerative disease states which respond to the modulation of NOGO and NOGO receptor expression. In one embodiment, a nucleic acid molecule that inhibits NOGO and/or NOGO receptor replication or expression can comprise between 12 and 100 bases complementary to a RNA molecule of NOGO or NOGO receptor, ta another embodiment, a nucleic acid molecule that inhibits NOGO or NOGO receptor replication or expression comprises between 14 and 24 bases complementary to a RNA molecule of NOGO or NOGO receptor.
ta one embodiment the invention provides a method for producing a class of nucleic acid-based gene inhibiting agents which exhibit a high degree of specificity for the RNA of a desired target. For example, the enzymatic nucleic acid molecule is preferably targeted to a highly conserved sequence region of target RNAs encoding NOGO-A, NOGO-B, NOGO-C and/or receptor proteins (specifically NOGO and NOGO receptor genes) such that specific treatment of a disease or condition can be provided with either one or several nucleic acid molecules of the invention. Such nucleic acid molecules can be delivered exogenously to specific tissue or cellular targets as required. Alternatively, the nucleic acid molecules {e.g., ribozymes and antisense) can be expressed from DNA and/or RNA vectors that are delivered to specific cells.
The nucleic acid-based inhibitors of NOGO and NOGO receptor expression are useful for the prevention and/or treatment of diseases and conditions such CNS injury, cerebrovascular accident (CVA, stroke), Alzheimer's disease, dementia, multiple sclerosis (MS), chemotherapy-induced neuropathy, muscular dystrophy and any other diseases or conditions that are related to or will respond to the levels of NOGO and/or NOGO receptor in a cell or tissue, alone or in combination with other therapies, ta addition, NOGO and/or NOGO receptor inhibition can be used as a therapeutic target for abrogating CNS neuronal growth inhibition; a situation that can selectively regenerate damaged or lesioned CNS tissue to restore specific reflex and/or locomotor functions.
ta a further embodiment, the described molecules, such as antisense, siRNA or ribozymes, can be used in combination with other known treatments to treat conditions or diseases discussed above. For example, the described molecules can be used in combination with one or more known therapeutic agents to treat CNS injury, spinal cord injury, cerebrovascular accident (CVA, stroke), Alzheimer's disease, dementia, multiple sclerosis (MS), chemotherapy-induced neuropathy, amyotrophic lateral sclerosis (ALS), Parkinson's disease, ataxia, Huntington's disease, Creutzfeldt- Jakob disease, muscular dystrophy, and/or other neurodegenerative disease states which respond to the modulation of NOGO and/or NOGO receptor expression.
ta another embodiment, the invention features nucleic acid-based inhibitors {e.g., enzymatic nucleic acid molecules (eg; ribozymes), antisense nucleic acids, 2-5A antisense chimeras, triplex DNA, antisense nucleic acids containing RNA cleaving chemical groups) and methods for their use to down regulate or inhibit the expression of genes {e.g., NOGO and/or NOGO receptor) capable of progression and or maintenance of CNS injury, spinal cord injury, cerebrovascular accident (CVA, stroke), Alzheimer's disease, dementia, multiple sclerosis (MS), chemotherapy-induced neuropathy, amyotrophic lateral sclerosis (ALS), Parkinson's disease, ataxia, Huntington's disease, Creutzfeldt-Jakob disease, muscular dystrophy, and/or other neurodegenerative disease states which respond to the modulation of NOGO and or NOGO receptor expression.
The lack of axon regeneration capacity in the adult CNS manifests as a limiting factor in the treatment of CNS injury, cerebrovascular accident (CVA, stroke), chemotherapy- induced neuropathy, and possibly in neurodegenerative diseases such as Alzheimer's disease, dementia, multiple sclerosis (MS), chemotherapy-induced neuropathy, amyotrophic lateral sclerosis (ALS), Parkinson's disease, ataxia, Huntington's disease, Creutzfeldt-Jakob disease, and or muscular dystrophy. Neuron growth inhibition results from physical barriers imposed by glial scars, a lack of neurotrophic factors, and growth-inhibitory molecules associated with myelin. The abrogation of neurite growth inhibition creates the potential to treat conditions for which there is currently no definitive medical intervention. The inhibition of NOGO (Genbank Accession No AB020693) and NOGO-66 receptor (Genbank Accession No. AF283463) is demonstrated in the following examples.
Identification of Potential Target Sites in Human NOGO RNA
The sequence of human NOGO and NOGO receptor genes are screened for accessible sites using a computer-folding algorithm. Regions of the RNA that do not form secondary folding stmctures and contained potential enzymatic nucleic acid molecule and or antisense binding/cleavage sites are identified. The sequences of these binding/cleavage sites are shown in Tables III- VII.
Selection of Enzymatic Nucleic Acid Cleavage Sites in Human NOGO and NOGO receptor RNA
Enzymatic nucleic acid molecule target sites are chosen by analyzing sequences of Human NOGO (Genbank accession No: AB020693) and prioritizing the sites on the basis of folding. Enzymatic nucleic acid molecules are designed that can bind each target and are individually analyzed by computer folding (Christoffersen et al, 1994 J. Mol. Struc Theochem, 311, 273; Jaeger et al, 1989, Proc. Natl. Acad. Sci. USA, 86, 7706) to assess whether the enzymatic nucleic acid molecule sequences fold into the appropriate secondary stmcture. Those enzymatic nucleic acid molecules with unfavorable intramolecular interactions between the binding arms and the catalytic core are eliminated from consideration. As noted below, varying binding arm lengths can be chosen to optimize activity. Generally, at least 5 bases on each arm are able to bind to, or otherwise interact with, the target RNA.
Chemical Synthesis and Purification of Ribozymes and Antisense for Efficient Cleavage and or blocking of NOGO and NOGO receptor RNA
Enzymatic nucleic acid molecules and antisense constmcts are designed to anneal to various sites in the RNA message. The binding arms ofthe enzymatic nucleic acid molecules are complementary to the target site sequences described above, while the antisense constmcts are fully complimentary to the target site sequences described above. The enzymatic nucleic acid molecules and antisense constmcts were chemically synthesized. The method of synthesis used followed the procedure for normal RNA synthesis as described above and in Usman et al, (1987 J. Am. Chem. Soc, 109, 7845), Scaringe et al, (1990 Nucleic Acids Res., 18, 5433) and Wincott et al, supra, and made use of common nucleic acid protecting and coupling groups, such as dimethoxytrityl at the 5'-end, and phosphoramidites at the 3'-end. The average stepwise coupling yields were typically >98%.
Enzymatic nucleic acid molecules and antisense constmcts are also synthesized from
DNA templates using bacteriophage T7 RNA polymerase (Milligan and Uhlenbeck, 1989, Methods Enzymol. 180, 51). Enzymatic nucleic acid molecules and antisense constmcts are purified by gel electrophoresis using general methods or are purified by high pressure liquid chromatography (HPLC; See Wincott et al, supra; the totality of which is hereby incoφorated herein by reference) and are resuspended in water. The sequences of the chemically synthesized enzymatic nucleic acid molecules used in this study are shown below in Table III- VII. The sequences of the chemically synthesized antisense constmcts used in this study are complimentary sequences to the Substrate sequences shown below as in Table III-VII.
Enzymatic nucleic acid molecule Cleavage of NOGO and NOGO receptor RNA Target in vitro
Enzymatic nucleic acid molecules targeted to the human NOGO RNA are designed and synthesized as described above. These enzymatic nucleic acid molecules can be tested for cleavage activity in vitro, for example, using the following procedure. The target sequences and the nucleotide location within the NOGO receptor RNA are given in Tables III-VII.
Cleavage Reactions: Full-length or partially full-length, internally-labeled target RNA for enzymatic nucleic acid molecule cleavage assay is prepared by in vitro transcription in the presence of [a-32p] CTP, passed over a G 50 Sephadex column by spin chromatography and used as substrate RNA without further purification. Alternately, substrates are 5'-32p-end labeled using T4 polynucleotide kinase enzyme. Assays are performed by pre-warming a 2X concentration of purified enzymatic nucleic acid molecule in enzymatic nucleic acid molecule cleavage buffer (50 mM Tris-HCl, pH 7.5 at 37°C, 10 mM MgCl2) and the cleavage reaction was initiated by adding the 2X enzymatic nucleic acid molecule mix to an equal volume of substrate RNA (maximum of 1-5 nM) that was also pre-warmed in cleavage buffer. As an o initial screen, assays are carried out for 1 hour at 37 C using a final concentration of either 40 nM or 1 mM enzymatic nucleic acid molecule, i.e., enzymatic nucleic acid molecule excess. The reaction is quenched by the addition of an equal volume of 95% formamide, 20 mM EDTA, 0.05% bromophenol blue and 0.05% xylene cyanol after which the sample is heated to 95 C for 2 minutes, quick chilled and loaded onto a denaturing polyacrylamide gel. Substrate RNA and the specific RNA cleavage products generated by enzymatic nucleic acid molecule cleavage are visualized on an autoradiograph ofthe gel. The percentage of cleavage is determined by Phosphor Imager® quantitation of bands representing the intact substrate and the cleavage products.
Nucleic acid inhibition of NOGO and NOGO receptor target RNA in vivo
Nucleic acid molecules targeted to the human NOGO and NOGO receptor RNA are designed and synthesized as described above. These nucleic acid molecules can be tested for cleavage activity in vivo, for example using the procedures described below. The target sequences and the nucleotide location within the NOGO receptor RNA are given in Tables III-VII.
Cell Culture
Spillmann et al, 1998, J. Biol. Chem., 273, 19283-19293, describe the purification and biochemical characterization of a high molecular mass protein of bovine spinal cord myelin (bNI-220) which exerts potent inhibition of neurite outgrowth of NGF-primed PC 12 cells and chick DRG cells. This protein can be used to inhibit spreading of 3T3 fibroblasts and to induce collapse of chick DRG growth cones. The monoclonal antibody, mAb EN-1, can be used to fully neutralize the inhibitory activity of bNT-220, which is a presumed NOGO gene product. As such, nucleic acid molecules of the instant invention directed at the inhibition of NOGO expression can be used in place of mAb FN-1 in studying the inhibition of bNI-220 in cell culture experiments described in detail by Spillmann et al, supra. Criteria used in these experiments include the evaluation of spreading behavior of 3T3 fibroblasts, the neurite outgrowth response of PC 12 cells, and the growth cone motility of chick DRG growth cones. Similarly, nucleic acid molecules of the instant invention that target NOGO or NOGO receptors can be used to evaluate inhibition of NOGO mediated activity in these cell types using the criteria described above. Fournier et al, 2001, Nature, 409, 341 describe a mouse clone of the NOGO-66 receptor which is expressed in non-neuronal COS-7 cells. The transfected COS-7 cell line expresses NOGO-66 receptor protein on the cell surface. An antisemm developed to the NOGO-66 receptor can be used to specifically stain NOGO-66 receptor expressing cells by immunohistochemical staining. As such, an assay for screening nucleic acid-based inhibitors of NOGO-66 receptor expression is provided.
Animal models
Bregman et al, 1995, Nature, 378, 498-501 and Z'Graggen et al, 1998, J. Neuroscience, 18, 4744, describe a rat based system for evaluating the role of myelin- associated neurite growth inhibitory proteins in vivo. Young adult Lewis rats receive a mid- thoracic microsurgical spinal cord lesion or a unilateral pyramidotomy. These animals are then treated with mAb IN-1 secreting hybridoma cell explants. A control population receive hybridoma explants which secrete horsreradish peroxidase (HRP) antibodies. Cyclosporin is used during the treatment period to allow hybridoma survival. Additional control rats receive either the spinal cord lesion without any further treatment or no lesion. After a 4-6 week recovery period, behavioral training is followed by the quantitative analysis of reflex and locomotor function. EN-1 treated animals demonstrate growth of corticospinal axons around the lesion site and into the spinal cord which persist past the longest time point of analysis (12 weeks). Furthermore, both reflex and locomotor function, including the functional recovery of fine motor control, is restored in EN-1 treated animals. As such, a robust animal model as described by Bregman et a I. supra and Z'Graggen et al, supra, can be used to evaluate nucleic acid molecules of the instant invention when used in place of or in conjunction with mAb IN-1 toward use as modulators of neurite growth inhibitor function (eg. NOGO and NOGO receptor) in vivo.
Indications
The nucleic acids of the present invention can be used to treat a patient having a condition associated with the level of NOGO or NOGO receptor. One method of treatment comprises contacting cells of a patient with a nucleic acid molecule of the present invention, under conditions suitable for said treatment. Delivery methods and other methods of administration have been discussed herein and are commonly known in the art. Particular degenerative and disease states that can be associated with NOGO and NOGO receptor expression modulation include, but are not limited to, CNS injury, specifically spinal cord injury, cerebrovascular accident (CVA, stroke), Alzheimer's disease, dementia, multiple sclerosis (MS), chemotherapy-induced neuropathy, amyotrophic lateral sclerosis (ALS), Parkinson's disease, ataxia, Huntington's disease, Creutzfeldt-Jakob disease, muscular dystrophy, and/or other neurodegenerative disease states which respond to the modulation of NOGO and NOGO receptor expression.
The present body of knowledge in NOGO research indicates the need for methods to assay NOGO activity and for compounds that can regulate NOGO expression for research, diagnostic, and therapeutic use.
Other treatment methods comprise contacting cells of a patient with a nucleic acid molecule of the present invention and further comprise the use of one or more drug therapies under conditions suitable for said treatment. The use of monoclonal antibody (eg; mAb IN-1) treatment, growth factors, antiinflammatory compounds, for example methylprednisolone, calcium blockers, apoptosis inhibiting compounds, for example GM-1 ganglioside, and physical therapies, for example treadmill therapy, are all non-limiting examples of methods that can be combined with or used in conjunction with the nucleic acid molecules {e.g. ribozymes and antisense molecules) of the instant invention. Those skilled in the art will recognize that other dmg compounds and therapies can be similarly be readily combined with the nucleic acid molecules of the instant invention {e.g. ribozymes and antisense molecules) are hence within the scope ofthe instant invention.
Diagnostic uses
The nucleic acid molecules of this invention {e.g., enzymatic nucleic acid molecules) can be used as diagnostic tools to examine genetic drift and mutations within diseased cells or to detect the presence of NOGO and/or NOGO receptor RNA in a cell. The close relationship between enzymatic nucleic acid molecule activity and the stmcture of the target RNA allows the detection of mutations in any region of the molecule which alters the base-pairing and three-dimensional stmcture of the target RNA. By using multiple enzymatic nucleic acid molecules described in this invention, one can map nucleotide changes which are important to RNA stmcture and function in vitro, as well as in cells and tissues. Cleavage of target RNAs with enzymatic nucleic acid molecules can be used to inhibit gene expression and define the role (essentially) of specified gene products in the progression of disease. In this manner, other genetic targets can be defined as important mediators ofthe disease. These experiments can lead to better treatment of the disease progression by affording the possibility of combinational therapies {e.g., multiple enzymatic nucleic acid molecules targeted to different genes, enzymatic nucleic acid molecules coupled with known small molecule inhibitors, or intermittent treatment with combinations of enzymatic nucleic acid molecules and/or other chemical or biological molecules). Other in vitro uses of enzymatic nucleic acid molecules of this invention are well known in the art, and include detection of the presence of mRNAs associated with NOGO-related condition. Such RNA is detected by determining the presence of a cleavage product after treatment with a enzymatic nucleic acid molecule using standard methodology.
In a specific example, enzymatic nucleic acid molecules which cleave only wild-type or mutant forms of the target RNA are used for the assay. The first enzymatic nucleic acid molecule is used to identify wild-type RNA present in the sample and the second enzymatic nucleic acid molecule is used to identify mutant RNA in the sample. As reaction controls, synthetic substrates of both wild-type and mutant RNA are cleaved by both enzymatic nucleic acid molecules to demonstrate the relative enzymatic nucleic acid molecule efficiencies in the reactions and the absence of cleavage of the "non-targeted" RNA species. The cleavage products from the synthetic substrates also serve to generate size markers for the analysis of wild-type and mutant RNAs in the sample population. Thus each analysis requires two enzymatic nucleic acid molecules, two substrates and one unknown sample which is combined into six reactions. The presence of cleavage products is determined using an RNAse protection assay so that full-length and cleavage fragments of each RNA can be analyzed in one lane of a polyacrylamide gel. It is not absolutely required to quantify the results to gain insight into the expression of mutant RNAs and putative risk of the desired phenotypic changes in target cells. The expression of mRNA whose protein product is implicated in the development of the phenotype (t.e., NOGO) is adequate to establish risk. If probes of comparable specific activity are used for both transcripts, then a qualitative comparison of RNA levels will be adequate and will decrease the cost ofthe initial diagnosis. Higher mutant form to wild-type ratios are correlated with higher risk whether RNA levels are compared qualitatively or quantitatively. The use of enzymatic nucleic acid molecules in diagnostic applications contemplated by the instant invention is more fully described in George et al, US Patent Nos. 5,834,186 and 5,741,679, Shih et al, US Patent No. 5,589,332, Nathan et al, US Patent No 5,871,914, Nathan and Ellington, International PCT publication No. WO 00/24931, and Sullenger et al, International PCT publication No. WO 99/29842.
Example 3: Nucleic acid inhibition of EKK-gamma and PKR target RNA
The invention features nucleic acid molecules, for example enzymatic nucleic acid molecules, antisense nucleic acid molecules, 2,5-A chimeras, decoys, siRNA, triplex oligonucleotides, siRNA and/or aptamers, and methods to modulate gene expression, for example, genes encoding a member of the IKB kinase EKK complex, such as EKK-alpha (EKKl), EKK-beta (EKK2), or EKK-gamma (IKKγ) and/or a protein kinase PKR protein, ta particular, the instant invention features nucleic-acid based molecules and methods to modulate the expression of EKK-gamma (EKKγ) and protein kinase PKR.
The invention features one or more nucleic acid-based molecules and methods that independently or in combination modulate the expression of gene(s) encoding a member of the IKB kinase EKK complex or PKR. In particular embodiments, the invention features nucleic acid-based molecules and methods that modulate the expression of a member of the IKB kinase EKK complex, for example IKK-alpha (EKK1), EKK-beta (EKK2), or EKK-gamma ( KKγ) and/or a protein kinase PKR protein, such as EKK-alpha (EKKl) gene (Genbank Accession No. NM_001278); EKK-beta (EKK2) gene, for example (Genbank Accession No.AF080158), EKK-gamma (EKKγ) gene, for example (Genbank Accession No. NM_003639), and protein kinase PKR gene, for example (Genbank Accession No. NM_002759).
In one embodiment, an enzymatic nucleic acid molecule of the invention comprises a sequence selected from the group consisting of SEQ ED NOs. 7056-7249. ta another embodiment, an enzymatic nucleic acid molecule of the invention comprises at least one binding arm wherein one or more of said binding arms comprises a sequence complementary to a sequence selected from the group consisting of SEQ ED NOs. 1024-4414. ta another embodiment, an antisense nucleic acid molecule or siRNA molecule of the invention comprises a sequence complementary to a sequence selected from the group consisting of SEQ ED NOs. 1024-4414. ta another embodiment, an nucleic acid molecule of the invention is adapted to treat cancer. In yet another embodiment, an enzymatic nucleic acid molecule of the invention has an endonuclease activity to cleave RNA having EKK-gamma or PKR sequence. In one embodiment, an enzymatic nucleic acid molecule of the invention is in an taozyme, Zinzyme, G-cleaver, Amberzyme, DNAzyme, or Hammerhead configuration.
In another embodiment, an taozyme of the invention comprises a sequence complementary to a sequence selected from the group consisting of SEQ ED NOs. 1218-1721 and 3051-3549. In another embodiment, an taozyme of the invention comprises a sequence selected from the group consisting of SEQ ED NOs. 7250-7753 and 9701-10199.
In another embodiment, a Zinzyme of the invention comprises a sequence complementary to a sequence selected from the group consisting of SEQ ED NOs. 1722-1998 and 3550-3768. In another embodiment, a Zinzyme ofthe invention comprises a sequence selected from the group consisting of SEQ ED NOs 7754-8030 and 10200-10418.
In another embodiment, an Amberzyme of the invention comprises a sequence selected from the group consisting of SEQ ED NOs 8441-9069 and 11001-11547. In another embodiment, a DNAzyme of the invention comprises a sequence selected from the group consisting of SEQ ED NOs 8031-8440 and 10419-11000. ta another embodiment, a Hammerhead of the invention comprises a sequence complementary to a sequence selected from the group consisting of SEQ ED NOs. 1024-1217 and 2420-3050. ta another embodiment, a Hammerhead of the invention comprises a sequence selected from the group consisting of SEQ ED NOs 7056-7249 and 9070-9700. ta one embodiment, a nucleic acid molecule of the invention comprises between 12 and 100 bases complementary to RNA having sequence of IKK-gamma or PKR. In another embodiment, a nucleic acid molecule of the invention comprises between 14 and 24 bases complementary to RNA having sequence of EKK-gamma or PKR.
In yet another embodiment, a nucleic acid molecule of the invention is chemically synthesized.
In another embodiment, a nucleic acid molecule or antisense nucleic acid molecule of the invention comprises at least one 2'-sugar modification, at least one nucleic acid base modification, or at least one phosphate backbone modification. ta one embodiment, the invention features a mammalian cell, for example a human cell, including an enzymatic nucleic acid molecule ofthe invention.
The present invention features method of down-regulating PKR activity in a cell, comprising contacting the cell with a nucleic acid molecule of the invention, under conditions suitable for down-regulating of PKR activity.
The present invention also features method of treatment of a patient having a condition associated with the level of PKR, comprising contacting cells of the patient with a nucleic acid molecule ofthe invention under conditions suitable for the treatment. The present invention features method of down-regulating EKK-gamma activity in a cell, comprising contacting the cell with a nucleic acid molecule of the invention, under conditions suitable for down-regulating of EKK-gamma activity.
The present invention also features method of treatment of a patient having a condition associated with the level of EKK-gamma, comprising contacting cells of the patient with the nucleic acid molecule ofthe invention, under conditions suitable for the treatment. ta one embodiment, a method of treatment of the invention comprises the use of one or more dmg therapies under conditions suitable for said treatment. The present invention features method of cleaving RNA comprising a sequence of PKR gene comprising contacting an enzymatic nucleic acid molecule of the invention with the RNA of a PKR gene under conditions suitable for the cleavage.
The present invention also features method of cleaving RNA comprising a sequence of EKK-gamma gene comprising contacting an enzymatic nucleic acid molecule ofthe invention with the RNA of an EKK-gamma gene under conditions suitable for the cleavage.
In one embodiment, a method of cleavage ofthe invention is carried out in the presence of a divalent cation, for example Mg2+. ta another embodiment, a nucleic acid molecule of the invention comprises a cap stmcture, wherein the cap stmcture is at the 5 '-end, or 3 '-end, or both the 5 '-end and the 3'- end, for example a 3',3'-linked or 5',5'-linked deoxyabasic derivative.
The present invention also features an expression vector comprising a nucleic acid sequence encoding at least one nucleic acid molecule the invention in a manner which allows expression ofthe nucleic acid molecule. In one embodiment, the invention features a mammalian cell, for example a human cell, including an expression vector contemplated by the invention. ta another embodiment, an expression vector of the invention further comprises a sequence for a nucleic acid molecule complementary to the RNA of a subunit of EKK-gamma or PKR. In yet another embodiment, an expression vector of the invention comprises a nucleic acid sequence encoding two or more nucleic acid molecules, which can be the same or different.
The present invention also features a method for treatment of cancer, for example breast cancer, lung cancer, prostate cancer, colorectal cancer, brain cancer, esophageal cancer, stomach cancer, bladder cancer, pancreatic cancer, cervical cancer, head and neck cancer, ovarian cancer, melanoma, lymphoma, glioma, or multidmg resistant cancer, comprising administering to a patient a nucleic acid molecule of the invention under conditions suitable for said treatment.
In one embodiment, a nucleic acid molecule of the invention comprises at least five ribose residues, at least ten 2'-O-methyl modifications, and a 3'- end modification such as a 3 '-3' inverted abasic moiety, and/or phosphorothioate linkages on at least three of the 5' terminal nucleotides. In another embodiment, other dmg therapies contemplated by the invention include monoclonal antibodies, EKK-gamma or PKR-specific inhibitors, chemotherapy, or radiation therapy.
Specific chemotherapy contemplated by the invention include paclitaxel, docetaxel, cisplatin, methotrexate, cyclophosphamide, doxombin, fluorouracil carboplatin, edatrexate, gemcitabine, or vinorelbine.
The invention also features a method for treatment of an inflammatory disease, for example rheumatoid arthritis, restenosis, asthma, Crohn's disease, diabetes, obesity, autoimmune disease, lupus, multiple sclerosis, transplant/graft rejection, gene therapy applications, ischemia/reperfusion injury, glomemlonephritis, sepsis, allergic airway inflammation, inflammatory bowel disease, or infection, comprising the step of administering to a patient a nucleic acid molecule of the invention under conditions suitable for the treatment.
The present invention features pharmaceutical compositions comprising the nucleic acid molecules ofthe invention in a pharmaceutically acceptable carrier.
The invention also features a method of administering to a cell, such as mammalian cell (e.g. human cell), where the cell can be in culture or in a mammal, such as a human, an enzymatic nucleic acid molecule or antisense molecule of the instant invention, comprising contacting the cell with the nucleic acid molecule under conditions suitable for such administration. The method of administration can be in the presence of a delivery reagent, for example a lipid, cationic lipid, phospholipid, or liposome.
The nucleic acid molecules that target specific sites in EKK-gamma or PKR-specific RNAs represent a therapeutic approach to treat a variety of inflammatory-related diseases and conditions, including but not limited to rheumatoid arthritis, restenosis, asthma, Crohn's disease, incontinentia pigmenti, diabetes, obesity, autoimmune disease, lupus, multiple sclerosis, transplant/graft rejection, gene therapy applications, ischemia/reperfusion injury (CNS and myocardial), glomemlonephritis, sepsis, allergic airway inflammation, inflammatory bowel disease, infection, and any other inflammatory disease or condition which respond to the modulation of EKK-gamma or PKR function.
The enzymatic nucleic acid molecules that cleave the specified sites in EKK-gamma or
PKR-specific RNAs also represent a therapeutic approach to treat a variety of cancers, including but not limited to breast, lung, prostate, colorectal, brain, esophageal, bladder, pancreatic, cervical, head and neck, and ovarian cancer, melanoma, lymphoma, glioma, multidmg resistant cancers, and/or other cancers which respond to the modulation of EKK- gamma or PKR function. In one embodiment, a nucleic acid molecule that modulates, for example, down- regulates EKK-gamma or PKR expression comprises between 12 and 100 bases complementary to a RNA molecule of EKK-gamma or PKR. In another embodiment, a nucleic acid molecule that modulates, for example EKK-gamma or PKR expression comprises between 14 and 24 bases complementary to a RNA molecule of EKK-gamma or PKR.
Nucleic acid-based inhibitors of EKK-gamma or PKR function are useful for the prevention and/or treatment of cancers and cancerous conditions such as breast, lung, prostate, colorectal, brain, esophageal, bladder, pancreatic, cervical, head and neck, and ovarian cancer, melanoma, lymphoma, glioma, multidmg resistant cancers, and any other diseases or conditions that are related to or will respond to the levels of EKK-gamma or PKR in a cell or tissue, alone or in combination with other therapies.
Nucleic acid-based inhibitors of EKK-gamma or PKR function are also useful for the prevention and/or treatment of inflammatory related diseases and conditions, including but not limited to rheumatoid arthritis, restenosis, asthma, Crohn's disease, incontinentia pigmenti, diabetes, obesity, autoimmune disease, lupus, multiple sclerosis, transplant/graft rejection, gene therapy applications, ischemia/reperfusion injury (CNS and myocardial), glomemlonephritis, sepsis, allergic airway inflammation, inflammatory bowel disease, infection, and any other inflammatory disease or condition which respond to the modulation of EKK-gamma or PKR function.
In a further embodiment, the described nucleic acid molecules, such as antisense, siRNA or enzymatic nucleic acid molecules, can be used in combination with other known treatments to treat conditions or diseases discussed above. For example, the described molecules can be used in combination with one or more known therapeutic agents to treat breast, lung, prostate, colorectal, brain, esophageal, bladder, pancreatic, cervical, head and neck, and ovarian cancer, melanoma, lymphoma, glioma, multidmg resistant cancers, rheumatoid arthritis, restenosis, asthma, Crohn's disease, diabetes, incontinentia pigmenti, obesity, autoimmune disease, lupus, multiple sclerosis, transplant/graft rejection, gene therapy applications, ischemia/reperfusion injury (CNS and myocardial), glomemlonephritis, sepsis, allergic airway inflammation, inflammatory bowel disease, infection, and any other cancerous disease or inflammatory disease or condition which respond to the modulation of EKK-gamma or PKR expression.
Identification of Potential Target Sites in Human EKK-gamma and PKR RNA
The sequence of human EKK-gamma or PKR genes are screened for accessible sites using a computer- folding algorithm. Regions of the RNA that do not form secondary folding stmctures and contained potential enzymatic nucleic acid molecule and/or antisense binding cleavage sites are identified. The sequences of these binding/cleavage sites are shown in Tables VIII-XVIII.
Selection of Enzymatic Nucleic Acid Cleavage Sites in Human EKK-gamma and PKR RNA
Enzymatic nucleic acid molecule target sites are chosen by analyzing sequences of Human EKK-gamma (Genbank accession No: NM 003639) and PKR (Genbank accession No: NM_002759) and prioritizing the sites on the basis of folding. Enzymatic nucleic acid molecules are designed that can bind each target and are individually analyzed by computer folding (Christoffersen et al, 1994 J. Mol. Struc. Theochem, 311, 273; Jaeger et al, 1989, Proc Natl. Acad. Sci. USA, 86, 7706) to assess whether the enzymatic nucleic acid molecule sequences fold into the appropriate secondary stmcture. Those enzymatic nucleic acid molecules with unfavorable intramolecular interactions between the binding arms and the catalytic core are eliminated from consideration. As noted below, varying binding arm lengths can be chosen to optimize activity. Generally, at least 5 bases on each arm are able to bind to, or otherwise interact with, the target RNA.
Chemical Synthesis and Purification of Ribozymes and Antisense for Efficient Cleavage and or blocking of EKK-gamma and PKR RNA
Enzymatic nucleic acid molecules and antisense constmcts are designed to anneal to various sites in the RNA message. The binding arms ofthe enzymatic nucleic acid molecules are complementary to the target site sequences described above, while the antisense constructs are fully complementary to the target site sequences described above. The enzymatic nucleic acid molecules and antisense constmcts were chemically synthesized. The method of synthesis used followed the procedure for normal RNA synthesis as described above and in Usman et al, (1987 J. Am. Chem. Soc, 109, 7845), Scaringe et al, (1990 Nucleic Acids Res., 18, 5433) and Wincott et al, supra, and made use of common nucleic acid protecting and coupling groups, such as dimethoxytrityl at the 5'-end, and phosphoramidites at the 3'-end. The average stepwise coupling yields were typically >98%.
Enzymatic nucleic acid molecules and antisense constructs are also synthesized from DNA templates using bacteriophage T7 RNA polymerase (Milligan and Uhlenbeck, 1989, Methods Enzymol. 180, 51). Enzymatic nucleic acid molecules and antisense constmcts are purified by gel electrophoresis using general methods or are purified by high pressure liquid chromatography (HPLC; See Wincott et al, supra; the totality of which is hereby incoφorated herein by reference) and are resuspended in water. The sequences of the chemically synthesized enzymatic nucleic acid molecules used in this study are shown below in Table XVIII. The sequences of the chemically synthesized antisense constmcts used in this study are complementary sequences to the Substrate sequences shown below as in Tables VIII-XVIII.
Enzymatic nucleic acid molecule Cleavage of EKK-gamma and PKR RNA Target in vitro
Enzymatic nucleic acid molecules targeted to the human IKK-gamma or PKR RNA are designed and synthesized as described above. These enzymatic nucleic acid molecules can be tested for cleavage activity in vitro, for example, using the following procedure. The target sequences and the nucleotide location within the EKK-gamma or PKR RNA are given in
Tables VIII-XVIII.
Cleavage Reactions: Full-length or partially full-length, internally-labeled target RNA for enzymatic nucleic acid molecule cleavage assay is prepared by in vitro transcription in the presence of [a-32p] CTP, passed over a G 50 Sephadex column by spin chromatography and used as substrate RNA without further purification. Alternately, substrates are 5'-32p-end labeled using T4 polynucleotide kinase enzyme. Assays are performed by pre-warming a 2X concentration of purified enzymatic nucleic acid molecule in enzymatic nucleic acid molecule cleavage buffer (50 mM Tris-HCl, pH 7.5 at 37°C, 10 mM MgCb) and the cleavage reaction was initiated by adding the 2X enzymatic nucleic acid molecule mix to an equal volume of substrate RNA (maximum of 1-5 nM) that was also pre-warmed in cleavage buffer. As an o initial screen, assays are carried out for 1 hour at 37 C using a final concentration of either 40 nM or 1 mM enzymatic nucleic acid molecule, i.e., enzymatic nucleic acid molecule excess. The reaction is quenched by the addition of an equal volume of 95%) formamide, 20 mM
EDTA, 0.05%) bromophenol blue and 0.05% xylene cyanol after which the sample is heated o to 95 C for 2 minutes, quick chilled and loaded onto a denaturing polyacrylamide gel. Substrate RNA and the specific RNA cleavage products generated by enzymatic nucleic acid molecule cleavage are visualized on an autoradiograph of the gel. The percentage of cleavage is determined by Phosphor Imager® quantitation of bands representing the intact substrate and the cleavage products.
Nucleic acid down-regulation of EKK-gamma and PKR target RNA in vivo
Nucleic acid molecules targeted to the human EKK-gamma or PKR RNA are designed and synthesized as described above. These nucleic acid molecules can be tested for cleavage activity in vivo, for example using the procedures described below. The target sequences and the nucleotide location within the EKK-gamma or PKR RNA are given in Tables VIII- XVIII.
In vivo models used to evaluate the down-regulation of EKK-gamma or PKR gene expression A variety of endpoints have been used in cell culture models to evaluate EKK-gamma or PKR-mediated effects after treatment with anti-EKK-gamma or PKR agents. Phenotypic endpoints include inhibition of cell proliferation, apoptosis assays and reduction of EKK- gamma or PKR protein expression, or a decrease in NFKB expression. Since IKK-gamma and PKR are both involved in the induction of NFKB, NFKB can be used as a surrogate marker in cell culture, animal, and clinical studies. Because overexpression of NFKB is directly associated with increased proliferation of tumor cells, a proliferation endpoint for cell culture assays is preferably used as a primary screen. There are several methods by which this endpoint can be measured. Following treatment of cells with nucleic acid molecules, cells are allowed to grow (typically 5 days) after which either the cell viability, the incoφoration of [3H] thymidine into cellular DNA and/or the cell density can be measured. The assay of cell density is very straightforward and can be performed in a 96-well format using commercially available fluorescent nucleic acid stains (such as Syto® 13 or CyQuant®). The assay using CyQuant® is described herein
As a secondary, confirmatory endpoint a nucleic acid-mediated decrease in the level of
EKK-gamma or PKR RNA and/or EKK-gamma or PKR protein expression can be evaluated. Alternately, a decrease in the level of NFKB RNA can be evaluated.
Cell Culture
Cell types that express/over-express NFKB include HeLa, macrophages, peripheral blood lymphocytes, hepatocytes, fibroblasts, endothelial cells and epithelial cells, ta culture, these cells can be stimulated to express/over-express NFKB by addition of TNF-alpha PMA or IL-1-beta to the culture medium. Some of these cell types also can respond with a similar activation of NFKB following LPS treatment. Activation of NFKB in cultured cells can be evaluated by electrophoretic mobility shift assay (EMSA). Delineation of alterations in the subunits can be determined by Western blot.
Primary Screen
A useful cell culture system in evaluating NFKB modulation is human colonic epithelial cells. One suitable cell line is SW620 colon carcinoma cells (CCL227). These cells respond to stimulation with TNF-alpha, LPS and/or EL- 1 -beta with an increase in NFKB activation. SW620 cells are grown in MEM supplemented with 10%> heat-inactivated FBS and glutamine (2 mmol/L).
TNF-alpha dose-response curves in these cells are determined by incubating cells with various concentrations of recombinant human TNF-alpha (Sigma Chemical Co.). Maximal DNA binding activity induction can occur with 150U/ml TNF-alpha in the culture medium. Induction is typically evident within 10 minutes of treatment with TNF-alpha reaches a peak at one hour post-treatment and persists for up to 4 hours post-treatment. The primary readout can be NFKB DNA activity in nuclear extracts of SW620 cells as determined by electrophoretic mobility shift assays (EMSA). Once the appropriate TNF-alpha dose/response profile has been determined, inhibition of EKK-gamma, PKR, or NFKB activation is evaluated using specific and non-specific inhibitors of activation, sulfasalazine and steroids, respectively. Cells are incubated with inhibitors or control media for 30 minutes prior to stimulation with TNF-alpha Nuclear extracts are prepared and evaluated for DNA binding activity by EMSA. Once the activity of positive controls has been established, enzymatic nucleic acids targeting the EKK-gamma or PKR are evaluated in this system. Supershift assays using polyclonal antibodies against the NFKB or PKR protein subunits can be performed to confirm down-regulation of NFKB.
Secondary Screens
SW620 cells can be transfected with the 3xIg-kappa-B-Luc reporter construct 18 hours before challenge with TNF-alpha, LPS or PMA. The readout for this assay is luciferase activity. Test compounds are applied 17.5 hours after transfection (30 minutes before challenge). Cells are harvested 24 hours after challenge and relative changes in luciferase activity is used as the endpoint. Lastly, the activation of NFKB can be visualized fluorescently. Inactive NFKB heterodimers are held in the cytoplasm by inhibitory proteins. Once activated, the free heterodimers translocate to the nucleus. Thus, the relative change in cytopiasmic versus nuclear fluorescence can indicate the degree of NFKB activation. Cells can be grown on chamber slides, treated with TNF-alpha with and without test compounds), and the location of the NFKB subunit can be determined by immunofluorescence using a FITC-labeled antibody to NFKB.
Animal Models
Evaluating the efficacy of anti-EKK-gamma or PKR agents in animal models is an important prerequisite to human clinical trials. Studies have shown that human breast carcinoma cell lines express high levels of NFKB (Sovak et al, 1997, J. Clin. Invest., 100, 2952-2960). High levels of NFKB have also been observed in carcinogen-induced primary rat mammary tumors and in human breast cancer specimins. Additionally, HER2/neu overexpression has been shown to activate NFKB (Pianetti et al, 2001, Oncogene, 20, 1287- 1299). As such, xenografts of cell lines that over-express NFKB can be used in animal models of tumorigenesis and or inflammation to study the inhibition of NFKB. Oncology Animal Model Development
Tumor cell lines are characterized to establish their growth curves in mice. These cell lines are implanted into both nude and SCED mice and primary tumor volumes are measured 3 times per week. Growth characteristics of these tumor lines using a Matrigel implantation format can also be established. The use of other cell lines that have been engineered to express high levels of NFKB can also be used in the described studies. The tumor cell line(s) and implantation method that supports the most consistent and reliable tumor growth is used in animal studies testing the lead IKK-gamma or PKR nucleic acid(s). Nucleic acids are administered by daily subcutaneous injection or by continuous subcutaneous infusion from Alzet mini osmotic pumps beginning 3 days after tumor implantation and continuing for the duration of the study. Group sizes of at least 10 animals are employed. Efficacy is determined by statistical comparison of tumor volume of nucleic acid-treated animals to a control group of animals treated with saline alone. Because the growth of these tumors is generally slow (45-60 days), an initial endpoint is the time in days it takes to establish an easily measurable primary tumor (i.e. 50-100 mm3) in the presence or absence of nucleic acid treatment.
Inflammation Animal Model Development
Chronic, sublethal administration of indomethacin to outbred rats produces an enteropathy characterized by thickening of the small intestine and mesentery, ulcerations, granulomatous inflammation, crypt abcesses and adhesions. These lesions are similar to those that are characteristic findings in human patients with Crohn's disease (CD). Thus, any beneficial therapeutic effects revealed using this model can be extrapolated to potential benefit for patients with CD.
Male Sprague-Dawley rats (200-275g) are utilized for these studies. Chronic intestinal inflammation is induced by two subcutaneous injections of indomethacin (7.5 mg/kg in 5%>
NaHCO3) administered on subsequent days (Day-0 and Day-1). Animals are followed for four days following the first indomethacin injection. The mortality rate associated with this model is typically less than 10%. On the last day ofthe study, animals are euthanized by CO2 asphyxiation, small intestines excised and gross pathologic findings ranked according to the following criteria: 0, normal ; 1, minimal abnormalities, slight thickening of the small intestine, no adhesions; 2, obvious thickening of small intestine with 1 adhesion; 3, obvious thickening of small intestine with 2 or 3 adhesions; 4, massive adhesions to the extent that the intestine cannot be separated, contents primarily fluid; 5, severe peritonitis resulting in death. A 10-cm portion of the most affected region of the small intestine is weighed, placed in 10%) neutral buffered formalin and submitted for histopatho logic evaluation. The 10 cm portion of gut from each animal is cut into five equal sections. Transverse and longitudinal sections of each portion are cut and stained with hematoxylin and eosin. All slides are read in a blinded fashion and each section is scored for necrosis (%> area of involvement) and inflammatory response according to the following scale:
Necrosis - 1, 10%; 2, 10-25%; 3, 25-50%; 4, 50-75%; 5, 75-100%;
Inflammation -
1= minimal in mesentery and muscle or lesion
2= mild in mesentery and muscle or lesion
3= moderate in mesentery and muscle or lesion
4— marked in lesion
5= severe in lesion
The scores for each ofthe five sections are averaged for necrosis and for inflammation.
NFKB Levels for Patient Screening and as a Potential Endpoint
Because elevated NFKB levels can be detected in cancers, cancer patients can be pre- screened for elevated NFKB prior to admission to initial clinical trials testing an anti-EKK- gamma or PKR nucleic acid. Initial NFKB levels can be determined (by ELISA) from tumor biopsies or resected tumor samples. During clinical trials, it can be possible to monitor circulating NFKB protein by ELISA. Evaluation of serial blood/serum samples over the course of the anti-EKK-gamma or PKR nucleic acid treatment period could be useful in determining early indications of efficacy.
Activity of nucleic acid molecules used to down-regulate EKK-gamma and PKR gene expression
Applicant has designed and synthesized several nucleic acid molecules targeted against EKK-gamma or PKR RNA. These nucleic acid molecules can be tested in cell proliferation and RNA reduction assays described herein.
Proliferation assay
A model proliferation assay can be done using a cell-plating density of 2,000-10,000 cells/well in 96-well plates and at least 2 cell doublings over a 5-day treatment period. Cells used in proliferation studies can be, for example, were either lung or ovarian cancer cells (A549 and SKON-3 cells respectively). To calculate cell density for proliferation assays, the FEPS (fluoro-imaging processing system) method known in the art can be used. This method allows for cell density measurements after nucleic acids are stained with CyQuant® dye, and has the advantage of accurately measuring cell densities over a very wide range 1,000- 100,000 cells/well in 96-well format. Enzymatic nucleic acid molecules (50-200 nM) are delivered in the presence of cationic lipid at 2.5-5.0 μg/mL and inhibition of proliferation can be determined on day 5 post-treatment.
RΝA assay
RΝA is harvested 24 hours post-treatment using the Qiagen RΝeasy® 96 procedure. Real time RT-PCR (TaqMan® assay) is performed on purified RΝA samples using separate primer/probe sets specific for target EKK-gamma or PKR RΝA.
indications
Particular degenerative and disease states that can be associated with EKK-gamma or PKR expression modulation include but are not limited to cancerous and or inflammatory diseases and conditions such as breast, lung, prostate, colorectal, brain, esophageal, bladder, pancreatic, cervical, head and neck, and ovarian cancer, melanoma, lymphoma, glioma, multidmg resistant cancers, rheumatoid arthritis, restenosis, asthma, Crohn's disease, diabetes, obesity, autoimmune disease, lupus, multiple sclerosis, transplant/graft rejection, gene therapy applications, ischemia/reperfusion injury (CΝS and myocardial), glomemlonephritis, sepsis, allergic airway inflammation, inflammatory bowel disease, infection, incontinentia pigmenti and any other diseases or conditions that are related to or respond to the levels of EKK-gamma or PKR in a cell or tissue. The present body of knowledge in EKK-gamma and PKR research indicates the need for methods to assay EKK- gamma and PKR activity and for compounds that can regulate EKK-gamma and PKR expression for research, diagnostic, and therapeutic use.
The use of monoclonal antibodies, chemotherapy, radiation therapy, analgesics, and/or anti-inflammatory compounds, are all non-limiting examples of a methods that can be combined with or used in conjunction with the nucleic acid molecules {e.g. ribozymes and antisense molecules) of the instant invention. Common chemotherapies that can be combined with nucleic acid molecules of the instant invention include various combinations of cytotoxic dmgs to kill cancer cells. These dmgs include but are not limited to paclitaxel (Taxol), docetaxel, cisplatin, methotrexate, cyclophosphamide, doxombin, fluorouracil carboplatin, edatrexate, gemcitabine, vinorelbine etc. Those skilled in the art will recognize that other dmg compounds and therapies can be similarly be readily combined with the nucleic acid molecules of the instant invention {e.g. ribozymes and antisense molecules) are hence within the scope ofthe instant invention.
Diagnostic uses
The nucleic acid molecules of this invention {e.g., enzymatic nucleic acid molecules) can be used as diagnostic tools to examine genetic drift and mutations within diseased cells or to detect the presence of EKK-gamma or PKR RNA in a cell. The close relationship between enzymatic nucleic acid molecule activity and the stmcture of the target RNA allows the detection of mutations in any region of the molecule which alters the base-pairing and three- dimensional stmcture ofthe target RNA. By using multiple enzymatic nucleic acid molecules described in this invention, one can map nucleotide changes which are important to RNA stmcture and function in vitro, as well as in cells and tissues. Cleavage of target RNAs with enzymatic nucleic acid molecules can be used to inhibit gene expression and define the role (essentially) of specified gene products in the progression of disease, ta this manner, other genetic targets can be defined as important mediators of the disease. These experiments can lead to better treatment of the disease progression by affording the possibility of combinational therapies {e.g., multiple enzymatic nucleic acid molecules targeted to different genes, enzymatic nucleic acid molecules coupled with known small molecule inhibitors, or intermittent treatment with combinations of enzymatic nucleic acid molecules and/or other chemical or biological molecules). Other in vitro uses of enzymatic nucleic acid molecules of this invention are well known in the art, and include detection of the presence of mRNAs associated with EKK-gamma or PKR-related condition. Such RNA is detected by determining the presence of a cleavage product after treatment with an enzymatic nucleic acid molecule using standard methodology.
ta a specific example, enzymatic nucleic acid molecules which cleave only wild-type or mutant forms of the target RNA are used for the assay. The first enzymatic nucleic acid molecule is used to identify wild-type RNA present in the sample and the second enzymatic nucleic acid molecule is used to identify mutant RNA in the sample. As reaction controls, synthetic substrates of both wild-type and mutant RNA are cleaved by both enzymatic nucleic acid molecules to demonstrate the relative enzymatic nucleic acid molecule efficiencies in the reactions and the absence of cleavage of the "non-targeted" RNA species. The cleavage products from the synthetic substrates also serve to generate size markers for the analysis of wild-type and mutant RNAs in the sample population. Thus each analysis requires two enzymatic nucleic acid molecules, two substrates and one unknown sample which is combined into six reactions. The presence of cleavage products is determined using an RNAse protection assay so that full-length and cleavage fragments of each RNA can be analyzed in one lane of a polyacrylamide gel. It is not absolutely required to quantify the results to gain insight into the expression of mutant RNAs and putative risk of the desired phenotypic changes in target cells. The expression of mRNA whose protein product is implicated in the development of the phenotype {i.e., EKK-gamma or PKR) is adequate to establish risk. If probes of comparable specific activity are used for both transcripts, then a qualitative comparison of RNA levels will be adequate and will decrease the cost ofthe initial diagnosis. Higher mutant form to wild-type ratios are correlated with higher risk whether RNA levels are compared qualitatively or quantitatively. The use of enzymatic nucleic acid molecules in diagnostic applications contemplated by the instant invention is more fully described in George et al, US Patent Nos. 5,834,186 and 5,741,679, Shih et al, US Patent No. 5,589,332, Nathan et al, US Patent No 5,871,914, Nathan and Ellington, International PCT publication No. WO 00/24931, Breaker et al, International PCT Publication Nos. WO 00/26226 and 98/27104, and Sullenger et al, International PCT publication No. WO 99/29842.
Additional Uses
Potential uses of sequence-specific enzymatic nucleic acid molecules of the instant invention can have many of the same applications for the study of RNA that DNA restriction endonucleases have for the study of DNA (Nathans et al, 1975 Ann. Rev. Biochem. 44:273). For example, the pattern of restriction fragments can be used to establish sequence relationships between two related RNAs, and large RNAs can be specifically cleaved to fragments of a size more useful for study. The ability to engineer sequence specificity of the enzymatic nucleic acid molecule is ideal for cleavage of RNAs of unknown sequence. Applicant has described the use of nucleic acid molecules to down-regulate gene expression of target genes in bacterial, microbial, fungal, viral, and eukaryotic systems including plant, or mammalian cells.
All patents and publications mentioned in the specification are indicative ofthe levels of skill of those skilled in the art to which the invention pertains. All references cited in this disclosure are incoφorated by reference to the same extent as if each reference had been incoφorated by reference in its entirety individually.
One skilled in the art would readily appreciate that the present invention is well adapted to carry out the objects and obtain the ends and advantages mentioned, as well as those inherent therein. The methods and compositions described herein as presently representative of preferred embodiments are exemplary and are not intended as limitations on the scope of the invention. Changes therein and other uses will occur to those skilled in the art, which are encompassed within the spirit ofthe invention, are defined by the scope ofthe claims. It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit of the invention. Thus, such additional embodiments are within the scope of the present invention and the following claims.
The invention illustratively described herein suitably can be practiced in the absence of any element or elements, limitation or limitations that is not specifically disclosed herein. Thus, for example, in each instance herein any of the terms "comprising", "consisting essentially of and "consisting of can be replaced with either of the other two terms. The terms and expressions that have been employed are used as terms of description and not of limitation, and there is no intention that in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments, optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by the description and the appended claims.
ta addition, where features or aspects of the invention are described in terms of Markush groups or other grouping of alternatives, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members ofthe Markush group or other group.
Other embodiments are within the following claims.
TABLE I
Characteristics of naturally occurring ribozymes
Group I Introns
Size: -150 to >1000 nucleotides.
• Requires a U in the target sequence immediately 5' of the cleavage site.
• Binds 4-6 nucleotides at the 5'-side of the cleavage site.
• Reaction mechanism: attack by the 3'-OH of guanosine to generate cleavage products with 3' -OH and 5' -guanosine.
• Additional protein cofactors required in some cases to help folding and maintenance of the active structure.
• Over 300 known members of this class. Found as an intervening sequence in Tetrahymena thermophila rRNA, fungal mitochondria, chloroplasts, phage T4, blue- green algae, and others.
• Major structural features largely established through phylogenetic comparisons, mutagenesis, and biochemical studies f1,"].
• Complete kinetic framework established for one ribozyme [ ,IV,v,V1].
• Studies of ribozyme folding and substrate docking underway [V11,V111,1X].
• Chemical modification investigation of important residues well established [X,X1] .
• The small (4-6 nt) binding site may make this ribozyme too non-specific for targeted RNA cleavage, however, the Tetrahymena group I intron has been used to repair a "defective" β-galactosidase message by the ligation of new β- galactosidase sequences onto the defective message [X11]. RNAse P RNA (Ml RNA)
Size: -290 to 400 nucleotides.
• RNA portion of a ubiquitous ribonucleoprotein enzyme.
• Cleaves tRNA precursors to form mature tRNA [X111].
• Reaction mechanism: possible attack by M 2+ -OH to generate cleavage products with 3'-OH and 5' -phosphate.
• RNAse P is found throughout the prokaryotes and eukaryotes. The RNA subunit has been sequenced from bacteria, yeast, rodents, and primates.
• Recruitment of endogenous RNAse P for therapeutic applications is possible through hybridization of an External Guide Sequence (EGS) to the target RNA
• Important phosphate and 2' OH contacts recently identified [xv^xvn]
Group II Introns
• Size: >1000 nucleotides.
• Trans cleavage of target RNAs recently demonstrated [χvm,χιχ].
• Sequence requirements not fully determined.
• Reaction mechanism: 2' -OH of an internal adenosine generates cleavage products with 3'-OH and a "lariat" RNA containing a 3' -5' and a 2' -5' branch point.
• Only natural ribozyme with demonstrated participation in DNA cleavage [χ ,xxl] in addition to RNA cleavage and ligation.
• Major structural features largely established through phylogenetic comparisons rxxiil
• Important 2' OH contacts beginning to be identified [ xm]
• Kinetic framework under development [xxιv] Neurospora VS RNA
Size: ~144 nucleotides.
Trans cleavage of hairpin target RNAs recently demonstrated [xxv].
Sequence requirements not fully determined.
Reaction mechanism: attack by 2' -OH 5' to the scissile bond to generate cleavage products with 2' ,3' -cyclic phosphate and 5' -OH ends.
Binding sites and structural requirements not fully determined.
Only 1 known member of this class. Found in Neurospora VS RNA.
Hammerhead Ribozyme
(see text for references)
Size: ~13 to 40 nucleotides.
Requires the target sequence UH immediately 5' of the cleavage site.
Binds a variable number nucleotides on both sides of the cleavage site.
Reaction mechanism: attack by 2' -OH 5' to the scissile bond to generate cleavage products with 2',3'-cyclic phosphate and 5' -OH ends.
14 known members of this class. Found in a number of plant pathogens (virusoids) that use RNA as the infectious agent.
Essential structural features largely defined, including 2 crystal structures [χχvi,χχv»]
Minimal ligation activity demonstrated (for engineering through in vitro selection) xxviiπ
Complete kinetic framework established for two or more ribozymes [xxix].
Chemical modification investigation of important residues well established [xxx]. Hairpin Ribozyme
• Size: ~50 nucleotides.
• Requires the target sequence GUC immediately 3' of the cleavage site.
• Binds 4-6 nucleotides at the 5'-side of the cleavage site and a variable number to the 3 '-side of the cleavage site.
• Reaction mechanism: attack by 2' -OH 5' to the scissile bond to generate cleavage products with 2',3'-cyclic phosphate and 5' -OH ends.
• 3 known members of this class. Found in three plant pathogen (satellite RNAs of the tobacco ringspot virus, arabis mosaic virus and chicory yellow mottle virus) which uses RNA as the infectious agent.
Essential structural features largely defined [χχχχ χχχm xxxιv]
• Ligation activity (in addition to cleavage activity) makes ribozyme amenable to engineering through in vitro selection [xxxv]
• Complete kinetic framework established for one ribozyme [xxxvl].
• Chemical modification investigation of important residues begun [χχ v»111].
Hepatitis Delta Virus (HDV) Ribozyme
• Size: ~60 nucleotides.
• Trans cleavage of target RNAs demonstrated [χ χιχ].
• Binding sites and structural requirements not fully determined, although no sequences 5' of cleavage site are required. Folded ribozyme contains a pseudoknot structure [x1].
• Reaction mechanism: attack by 2' -OH 5' to the scissile bond to generate cleavage products with 2' ,3' -cyclic phosphate and 5' -OH ends.
• Only 2 known members of this class. Found in human HDV.
• Circular form of HDV is active and shows increased nuclease stability [xh] I . Michel, Francois; Westhof, Eric. Slippery substrates. Nat. Struct. Biol. (1994), 1(1), 5-7.
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*' . Strobel, Scott A.; Cech, Thomas R.. Exocyclic Amine of the Conserved G.cntdot.U Pair at the
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M.. A group II intron RNA is a catalytic component of a DNA endonuclease involved in intron mobility. Cell (Cambridge, Mass.) (1995), 83(4), 529-38. xxl . Griffin, Edmund A., Jr.; Qin, Zhifeng; Michels, Williams J., Jr.; Pyle, Anna Marie. Group II intron ribozymes that cleave DNA and RNA linkages with similar efficiency, and lack contacts with substrate 2'- hydroxyl groups. Chem. Biol. (1995), 2(11), 761-70. x" . Michel, Francois; Ferat, Jean Luc. Structure and activities of group II introns. Annu. Rev. Biochem. (1995), 64, 435-61. xxl" . Abramovitz, Dana L.; Friedman, Richard A.; Pyle, Anna Marie. Catalytic role of 2 -hydroxyl groups within a group II intron active site. Science (Washington, D. C.) (1996), 271(5254), 1410-13. x ιv . Daniels, Danette L.; Michels, William J., Jr.; Pyle, Anna Marie. Two competing pathways for self- splicing by group II introns: a quantitative analysis of in vitro reaction rates and products. J. Mol. Biol. (1996), 256(1), 31-49. xv . Guo, Hans C. T.; Collins, Richard A.. Efficient trans-cleavage of a stem-loop RNA substrate by a ribozyme derived from Neurospora VS RNA. EMBO J. (1995), 14(2), 368-76. XV1 . Scott, W.G., Finch, J.T., Aaron,K. The crystal structure of an all RNA hammerhead ribozyme:Aproposed mechanism for RNA catalytic cleavage. Cell, (1995), 81, 991-1002. xx π McKay, Structure and function of the hammerhead ribozyme: an unfinished story. RNA, (1996), 2, 395-403.
X V1" . Long, D., Uhlenbeck, O., Hertel, K. Ligation with hammerhead ribozymes. US Patent No. 5,633,133. ,x . Hertel, K.J., Herschlag, D., Uhlenbeck, O. A kinetic and thermodynamic framework for the hammerhead ribozyme reaction. Biochemistry, (1994) 33, 3374-3385.Beigelman, L., et al, Chemical modifications of hammerhead ribozymes. J. Biol. Chem., (1995) 270, 25702-25708. xxx . Beigelman, L., et al, Chemical modifications of hammerhead ribozymes. J. Biol. Chem., (1995) 270, 25702-25708. . Hampel, Arnold; Tritz, Richard; Hicks, Margaret; Cruz, Phillip. 'Hairpin' catalytic RNA model: evidence for helixes and sequence requirement for substrate RNA. Nucleic Acids Res. (1990), 18(2), 299- 304. xx" . Chowrira, Bharat M.; Berzal-Herranz, Alfredo; Burke, John M.. Novel guanosine requirement for catalysis by the hairpin ribozyme. Nature (London) (1991), 354(6351), 320-2. x xui Berzal-Herranz, Alfredo; Joseph, Simpson; Chowrira, Bharat M.; Butcher, Samuel E.; Burke, John M.. Essential nucleotide sequences and secondary structure elements of the hairpin ribozyme. EMBO J. (1993), 12(6), 2567-73.
XXXIV . Joseph, Simpson; Berzal-Herranz, Alfredo; Chowrira, Bharat M.; Butcher, Samuel E.. Substrate selection rules for the hairpin ribozyme determined by in vitro selection, mutation, and analysis of mismatched substrates. Genes Dev. (1993), 7(1), 130-8. XXV . Berzal-Herranz, Alfredo; Joseph, Simpson; Burke, John M.. In vitro selection of active hairpin ribozymes by sequential RNA-catalyzed cleavage and ligation reactions. Genes Dev. (1992), 6(1), 129-34. xxxvi Hegg, Lisa A.; Fedor, Martha J.. Kinetics and Thermodynamics of Intermolecular Catalysis by Hairpin Ribozymes. Biochemistry (1995), 34(48), 15813-28. xxvu Grasby, Jane A.; Mersmann, Karin; Singh, Mohinder; Gait, Michael J.. Purine Functional Groups in Essential Residues of the Hairpin Ribozyme Required for Catalytic Cleavage of RNA. Biochemistry (1995), 34(12), 4068-76. xxviπ Schmidt, Sabine; Beigelman, Leonid; Karpeisky, Alexander; Usman, Nassim; Sorensen, Ulrik S.; Gait, Michael J.. Base and sugar requirements for RNA cleavage of essential nucleoside residues in internal loop B of the hairpin ribozyme: implications for secondary structure. Nucleic Acids Res. (1996), 24(4), 573-81. xxxix Perrotta, Anne T.; Been, Michael D.. Cleavage of oligoribonucleotides by a ribozyme derived from the hepatitis .delta, virus RNA sequence. Biochemistry (1992), 31(1), 16-21. xl . Perrotta, Anne T.; Been, Michael D.. A pseudoknot-like structure required for efficient self- cleavage of hepatitis delta virus RNA. Nature (London) (1991), 350(6317), 434-6. xh . Puttaraju, M.; Perrotta, Anne T.; Been, Michael D.. A circular trans-acting hepatitis delta virus ribozyme. Nucleic Acids Res. (1993), 21(18), 4253-8. Table II:
Figure imgf000098_0001
Wait time does not include contact time during delivery. Table III: Human NOGO Receptor Hammerhead Ribozyme and Substrate Sequence
Pos Substratβ Seq Ribozyme Rz
ID Seq
ID
10 CAACCCCU A CGAUGAAG 1 CUUCAUCG CUGAUGAGGCCGUUAGGCCGAA AGGGGUUG 5484
26 GAGGGCGU C CGCUGGAG 2 CUCCAGCG CUGAUGAGGCCGUUAGGCCGAA ACGCCCUC 5485
108 GCCUGCGU A UGCUACAA 3 UUGUAGCA CUGAUGAGGCCGUUAGGCCGAA ACGCAGGC 5486
113 CGUAUGCU A CAAUGAGC 4 GCUCAUUG CUGAUGAGGCCGUUAGGCCGAA AGCAUACG 5487
177 GUGGGCAU C CCUGCUGC 5 GCAGCAGG CUGAUGAGGCCGUUAGGCCGAA AUGCCCAC 5488
198 CAGCGCAU C UUCCUGCA 6 UGCAGGAA CUGAUGAGGCCGUUAGGCCGAA AUGCGCUG 5489
200 GCGCAUCU U CCUGCACG 7 CGUGCAGG CUGAUGAGGCCGUUAGGCCGAA AGAUGCGC 5490
201 CGCAUCUU C CUGCACGG 8 CCGUGCAG CUGAUGAGGCCGUUAGGCCGAA AAGAUGCG 5491
219 AACCGCAU C UCGCAUGU 9 ACAUGCGA CUGAUGAGGCCGUUAGGCCGAA AUGCGGUU 5492
221 CCGCAUCU C GCAUGUGC 10 GCACAUGC CUGAUGAGGCCGUUAGGCCGAA AGAUGCGG 5493
242 UGCCAGCU U CCGUGCCU 11 AGGCACGG CUGAUGAGGCCGUUAGGCCGAA AGCUGGCA 5494
243 GCCAGCUU C CGUGCCUG 12 CAGGCACG CUGAUGAGGCCGUUAGGCCGAA AAGCUGGC 5495
261 CGCAACCU C ACCAUCCU 13 AGGAUGGU CUGAUGAGGCCGUUAGGCCGAA AGGUUGCG 5496
267 CUCACCAU C CUGUGGCU 14 AGCCACAG CUGAUGAGGCCGUUAGGCCGAA AUGGUGAG 5497
281 GCUGCACU C GAAUGUGC 15 GCACAUUC CUGAUGAGGCCGUUAGGCCGAA AGUGCAGC 5498
300 GCCCGAAU U GAUGCGGC 16 GCCGCAUC CUGAUGAGGCCGUUAGGCCGAA AUUCGGGC 5499
314 GGCUGCCU U CACUGGCC 17 GGCCAGUG CUGAUGAGGCCGUUAGGCCGAA AGGCAGCC 5500
315 GCUGCCUU C ACUGGCCU 18 AGGCCAGU CUGAUGAGGCCGUUAGGCCGAA AAGGCAGC 5501
330 CUGGCCCU C CUGGAGCA 19 UGCUCCAG CUGAUGAGGCCGUUAGGCCGAA AGGGCCAG 5502
348 CUGGACCU C AGCGAUAA 20 UUAUCGCU CUGAUGAGGCCGUUAGGCCGAA AGGUCCAG 5503
355 UCAGCGAU A AUGCACAG 21 CUGUGCAU CUGAUGAGGCCGUUAGGCCGAA AUCGCUGA 5504
366 GCACAGCU C CGGUCUGU 22 ACAGACCG CUGAUGAGGCCGUUAGGCCGAA AGCUGUGC 5505
371 GCUCCGGU C UGUGGACC 23 GGUCCACA CUGAUGAGGCCGUUAGGCCGAA ACCGGAGC 5506
389 UGCCACAU U CCACGGCC 2 GGCCGUGG CUGAUGAGGCCGUUAGGCCGAA AUGUGGCA 5507
390 GCCACAUU C CACGGCCU 25 AGGCCGUG CUGAUGAGGCCGUUAGGCCGAA AAUGUGGC 5508
408 GGCCGCCU A CACACGCU 26 AGCGUGUG CUGAUGAGGCCGUUAGGCCGAA AGGCGGCC 5509
461 GGGGCUGU U CCGCGGCC 27 GGCCGCGG CUGAUGAGGCCGUUAGGCCGAA ACAGCCCC 5510
462 GGGCUGUU C CGCGGCCU 28 AGGCCGCG CUGAUGAGGCCGUUAGGCCGAA AACAGCCC 5511
485 CCUGCAGU A CCUCUACC 29 GGUAGAGG CUGAUGAGGCCGUUAGGCCGAA ACUGCAGG 5512
489 CAGUACCU C UACCUGCA 30 UGCAGGUA CUGAUGAGGCCGUUAGGCCGAA AGGUACUG 5513
491 GUACCUCU A CCUGCAGG 31 CCUGCAGG CUGAUGAGGCCGUUAGGCCGAA AGAGGUAC 5514
533 UGACACCU U CCGCGACC 32 GGUCGCGG CUGAUGAGGCCGUUAGGCCGAA AGGUGUCA 5515
534 GACACCUU C CGCGACCU 33 AGGUCGCG CUGAUGAGGCCGUUAGGCCGAA AAGGUGUC 5516
552 GGCAACCU C ACACACCU 34 AGGUGUGU CUGAUGAGGCCGUUAGGCCGAA AGGUUGCC 5517
561 ACACACCU C UUCCUGCA 35 UGCAGGAA CUGAUGAGGCCGUUAGGCCGAA AGGUGUGU 5518
563 ACACCUCU U CCUGCACG 36 CGUGCAGG CUGAUGAGGCCGUUAGGCCGAA AGAGGUGU 5519
564 CACCUCUU C CUGCACGG 37 CCGUGCAG CUGAUGAGGCCGUUAGGCCGAA AAGAGGUG 5520
582 AACCGCAU C UCCAGCGU 38 ACGCUGGA CUGAUGAGGCCGUUAGGCCGAA AUGCGGUU 5521
584 CCGCAUCU C CAGCGUGC 39 GCACGCUG CUGAUGAGGCCGUUAGGCCGAA AGAUGCGG 5522
605 GCGCGCCU U CCGUGGGC 0 GCCCACGG CUGAUGAGGCCGUUAGGCCGAA AGGCGCGC 5523
606 CGCGCCUU C CGUGGGCU 41 AGCCCACG CUGAUGAGGCCGUUAGGCCGAA AAGGCGCG 5524
624 CACAGCCU C GACCGUCU 42 AGACGGUC CUGAUGAGGCCGUUAGGCCGAA AGGCUGUG 5525
631 UCGACCGU C UCCUACUG 43 CAGUAGGA CUGAUGAGGCCGUUAGGCCGAA ACGGUCGA 5526
633 GACCGUCU C CUACUGCA 44 UGCAGUAG CUGAUGAGGCCGUUAGGCCGAA AGACGGUC 5527
636 CGUCUCCU A CUGCACCA 45 UGGUGCAG CUGAUGAGGCCGUUAGGCCGAA AGGAGACG 5528 677 GCAUGCCU U CCGUGACC 46 GGUCACGG CUGAUGAGGCCGUUAGGCCGAA AGGCAUGC 5529
678 CAUGCCUU C CGUGACCU 47 AGGUCACG CUGAUGAGGCCGUUAGGCCGAA AAGGCAUG 5530
687 CGUGACCU U GGCCGCCU 48 AGGCGGCC CUGAUGAGGCCGUUAGGCCGAA AGGUCACG 5531
696 GGCCGCCU C AUGACACU 49 AGUGUCAU CUGAUGAGGCCGUUAGGCCGAA AGGCGGCC 5532
705 AUGACACU C UAUCUGUU 50 AACAGAUA CUGAUGAGGCCGUUAGGCCGAA AGUGUCAU 5533
707 GACACUCU A UCUGUUUG 51 CAAACAGA CUGAUGAGGCCGUUAGGCCGAA AGAGUGUC 5534
709 CACUCUAU C UGUUUGCC 52 GGCAAACA CUGAUGAGGCCGUUAGGCCGAA AUAGAGUG 5535
713 CUAUCUGU U UGCCAACA 53 UGUUGGCA CUGAUGAGGCCGUUAGGCCGAA ACAGAUAG 5536
714 UAUCUGUU U GCCAACAA 54 UUGUUGGC CUGAUGAGGCCGUUAGGCCGAA AACAGAUA 5537
724 CCAACAAU C UAUCAGCG 55 CGCUGAUA CUGAUGAGGCCGUUAGGCCGAA AUUGUUGG 5538
726 AACAAUCU A UCAGCGCU 56 AGCGCUGA CUGAUGAGGCCGUUAGGCCGAA AGAUUGUU 5539
728 CAAUCUAU C AGCGCUGC 57 GCAGCGCU CUGAUGAGGCCGUUAGGCCGAA AUAGAUUG 5540
773 CCUGCAGU A CCUGAGGC 58 GCCUCAGG CUGAUGAGGCCGUUAGGCCGAA ACUGCAGG 5541
783 CUGAGGCU C AACGACAA 59 UUGUCGUU CUGAUGAGGCCGUUAGGCCGAA AGCCUCAG 5542
825 CGCCCACU C UGGGCCUG 60 CAGGCCCA CUGAUGAGGCCGUUAGGCCGAA AGUGGGCG 5543
845 GCAGAAGU U CCGCGGCU 61 AGCCGCGG CUGAUGAGGCCGUUAGGCCGAA ACUUCUGC 554
846 CAGAAGUU C CGCGGCUC 62 GAGCCGCG CUGAUGAGGCCGUUAGGCCGAA AACUUCUG 5545
854 CCGCGGCU C CUCCUCCG 63 CGGAGGAG CUGAUGAGGCCGUUAGGCCGAA AGCCGCGG 5546
857 CGGCUCCU C CUCCGAGG 64 CCUCGGAG CUGAUGAGGCCGUUAGGCCGAA AGGAGCCG 5547
860 CUCCUCCU C CGAGGUGC 65 GCACCUCG CUGAUGAGGCCGUUAGGCCGAA AGGAGGAG 5548
879 UGCAGCCU C CCGCAACG 66 CGUUGCGG CUGAUGAGGCCGUUAGGCCGAA AGGCUGCA 5549
906 CGUGACCU C AAACGCCU 67 AGGCGUUU CUGAUGAGGCCGUUAGGCCGAA AGGUCACG 5550
915 AAACGCCU A GCUGCCAA 68 UUGGCAGC CUGAUGAGGCCGUUAGGCCGAA AGGCGUUU 5551
958 CCGGCCCU U ACCAUCCC 69 GGGAUGGU CUGAUGAGGCCGUUAGGCCGAA AGGGCCGG 5552
959 CGGCCCUU A CCAUCCCA 70 UGGGAUGG CUGAUGAGGCCGUUAGGCCGAA AAGGGCCG 5553
964 CUUACCAU C CCAUCUGG 71 CCAGAUGG CUGAUGAGGCCGUUAGGCCGAA AUGGUAAG 5554
969 CAUCCCAU C UGGACCGG 72 CCGGUCCA CUGAUGAGGCCGUUAGGCCGAA AUGGGAUG 5555
1008 CUGGGGCU U CCCAAGUG 73 CACUUGGG CUGAUGAGGCCGUUAGGCCGAA AGCCCCAG 5556
1009 UGGGGCUU C CCAAGUGC 74 GCACUUGG CUGAUGAGGCCGUUAGGCCGAA AAGCCCCA 5557
1046 CAAGGCCU C AGUACUGG 75 CCAGUACU CUGAUGAGGCCGUUAGGCCGAA AGGCCUUG 5558
1050 GCCUCAGU A CUGGAGCC 76 GGCUCCAG CUGAUGAGGCCGUUAGGCCGAA ACUGAGGC 5559
1072 GACCAGCU U CGGCAGGC 77 GCCUGCCG CUGAUGAGGCCGUUAGGCCGAA AGCUGGUC 5560
1073 ACCAGCUU C GGCAGGCA 78 UGCCUGCC CUGAUGAGGCCGUUAGGCCGAA AAGCUGGU 5561
1133 CAACGGCU C UGGCCCAC 79 GUGGGCCA CUGAUGAGGCCGUUAGGCCGAA AGCCGUUG 5562
1149 CGGCACAU C AAUGACUC 80 GAGUCAUU CUGAUGAGGCCGUUAGGCCGAA AUGUGCCG 5563
1157 CAAUGACU C ACCCUUUG 81 CAAAGGGU CUGAUGAGGCCGUUAGGCCGAA AGUCAUUG 5564
1163 CUCACCCU U UGGGACUC 82 GAGUCCCA CUGAUGAGGCCGUUAGGCCGAA AGGGUGAG 5565
1164 UCACCCUU u GGGACUCU 83 AGAGUCCC CUGAUGAGGCCGUUAGGCCGAA AAGGGUGA 5566
1171 UUGGGACU C UGCCUGGC 84 GCCAGGCA CUGAUGAGGCCGUUAGGCCGAA AGUCCCAA 5567
1181 GCCUGGCU C UGCUGAGC 85 GCUCAGCA CUGAUGAGGCCGUUAGGCCGAA AGCCAGGC 5568
1197 CCCCCGCU c ACUGCAGU 86 ACUGCAGU CUGAUGAGGCCGUUAGGCCGAA AGCGGGGG 5569
1220 CGAGGGCU c CGAGCCAC 87 GUGGCUCG CUGAUGAGGCCGUUAGGCCGAA AGCCCUCG 5570
1235 ACCAGGGU u CCCCACCU 88 AGGUGGGG CUGAUGAGGCCGUUAGGCCGAA ACCCUGGU 5571
1236 CCAGGGUU c CCCACCUC 89 GAGGUGGG CUGAUGAGGCCGUUAGGCCGAA AACCCUGG 5572
1244 CCCCACCU c GGGCCCUC 90 GAGGGCCC CUGAUGAGGCCGUUAGGCCGAA AGGUGGGG 5573
1252 CGGGCCCU c GCCGGAGG 91 CCUCCGGC CUGAUGAGGCCGUUAGGCCGAA AGGGCCCG 557
1270 CAGGCUGU u CACGCAAG 92 CUUGCGUG CUGAUGAGGCCGUUAGGCCGAA ACAGCCUG 5575
1271 AGGCUGUU c ACGCAAGA 93 UCUUGCGU CUGAUGAGGCCGUUAGGCCGAA AACAGCCU 5576
1303 ACUGCCGU c UGGGCCAG 94 CUGGCCCA CUGAUGAGGCCGUUAGGCCGAA ACGGCAGU 5577
1343 UGGUGACU c AGAAGGCU 95 AGCCUUCU CUGAUGAGGCCGUUAGGCCGAA AGUCACCA 5578
1352 AGAAGGCU c AGGUGCCC 96 GGGCACCU CUGAUGAGGCCGUUAGGCCGAA AGCCUUCU 5579
Figure imgf000101_0001
D D Input Sequence = AB020693. Cut Site = CH/.
Arm Length = 8. Core Sequence = CUGAUGAG GCCGUUAGGC CGAA
AB020693 (Homo sapiens mRNA for KIAA0886 protein (Nogo-A); 4053 bp)
D
Underlined region can be any X sequence or linker, as described herein.
Table IV: Human NOGO Receptor Inozyme and Substrate Sequence
Pos Substrate Seq Inozyme Rz ID Seq
ID
9 CCAACCCC U ACGAUGAA 101 UUCAUCGU CUGAUGAGGCCGUUAGGCCGAA IGGGUUGG 5584
27 AGGGCGUC C GCUGGAGG 102 CCUCCAGC CUGAUGAGGCCGUUAGGCCGAA IACGCCCU 5585
30 GCGUCCGC U GGAGGGAG 103 CUCCCUCC CUGAUGAGGCCGUUAGGCCGAA ICGGACGC 5586
40 GAGGGAGC C GGCUGCUG 104 CAGCAGCC CUGAUGAGGCCGUUAGGCCGAA ICUCCCUC 5587
44 GAGCCGGC U GCUGGCAU 105 AUGCCAGC CUGAUGAGGCCGUUAGGCCGAA ICCGGCUC 5588
47 CCGGCUGC U GGCAUGGG 106 CCCAUGCC CUGAUGAGGCCGUUAGGCCGAA ICAGCCGG 5589
51 CUGCUGGC A UGGGUGCU 107 AGCACCCA CUGAUGAGGCCGUUAGGCCGAA ICCAGCAG 5590
59 AUGGGUGC U GUGGCUGC 108 GCAGCCAC CUGAUGAGGCCGUUAGGCCGAA ICACCCAU 5591
65 GCUGUGGC U GCAGGCCU 109 AGGCCUGC CUGAUGAGGCCGUUAGGCCGAA ICCACAGC 5592
68 GUGGCUGC A GGCCUGGC 110 GCCAGGCC CUGAUGAGGCCGUUAGGCCGAA ICAGCCAC 5593
72 CUGCAGGC C UGGCAGGU 111 ACCUGCCA CUGAUGAGGCCGUUAGGCCGAA ICCUGCAG 5594
73 UGCAGGCC U GGCAGGUG 112 CACCUGCC CUGAUGAGGCCGUUAGGCCGAA IGCCUGCA 5595
77 GGCCUGGC A GGUGGCAG 113 CUGCCACC CUGAUGAGGCCGUUAGGCCGAA ICCAGGCC 5596
84 CAGGUGGC A GCCCCAUG 114 CAUGGGGC CUGAUGAGGCCGUUAGGCCGAA ICCACCUG 5597
87 GUGGCAGC C CCAUGCCC 115 GGGCAUGG CUGAUGAGGCCGUUAGGCCGAA ICUGCCAC 5598
88 UGGCAGCC C CAUGCCCA 116 UGGGCAUG CUGAUGAGGCCGUUAGGCCGAA IGCUGCCA 5599
89 GGCAGCCC C AUGCCCAG 117 CUGGGCAU CUGAUGAGGCCGUUAGGCCGAA IGGCUGCC 5600
90 GCAGCCCC A UGCCCAGG 118 CCUGGGCA CUGAUGAGGCCGUUAGGCCGAA IGGGCUGC 5601
94 CCCCAUGC C CAGGUGCC 119 GGCACCUG CUGAUGAGGCCGUUAGGCCGAA ICAUGGGG 5602
95 CCCAUGCC C AGGUGCCU 120 AGGCACCU CUGAUGAGGCCGUUAGGCCGAA IGCAUGGG 5603
96 CCAUGCCC A GGUGCCUG 121 CAGGCACC CUGAUGAGGCCGUUAGGCCGAA IGGCAUGG 5604
102 CCAGGUGC C UGCGUAUG 122 CAUACGCA CUGAUGAGGCCGUUAGGCCGAA ICACCUGG 5605
103 CAGGUGCC U GCGUAUGC 123 GCAUACGC CUGAUGAGGCCGUUAGGCCGAA IGCACCUG 5606
112 GCGUAUGC U ACAAUGAG 124 CUCAUUGU CUGAUGAGGCCGUUAGGCCGAA ICAUACGC 5607
115 UAUGCUAC A AUGAGCCC 125 GGGCUCAU CUGAUGAGGCCGUUAGGCCGAA IUAGCAUA 5608
122 CAAUGAGC C CAAGGUGA 126 UCACCUUG CUGAUGAGGCCGUUAGGCCGAA ICUCAUUG 5609
123 AAUGAGCC C AAGGUGAC 127 GUCACCUU CUGAUGAGGCCGUUAGGCCGAA IGCUCAUU 5610
124 AUGAGCCC A AGGUGACG 128 CGUCACCU CUGAUGAGGCCGUUAGGCCGAA IGGCUCAU 5611
135 GUGACGAC A AGCUGCCC 129 GGGCAGCU CUGAUGAGGCCGUUAGGCCGAA IUCGUCAC 5612
139 CGACAAGC U GCCCCCAG 130 CUGGGGGC CUGAUGAGGCCGUUAGGCCGAA ICUUGUCG 5613
142 CAAGCUGC C CCCAGCAG 131 CUGCUGGG CUGAUGAGGCCGUUAGGCCGAA ICAGCUUG 5614
143 AAGCUGCC C CCAGCAGG 132 CCUGCUGG CUGAUGAGGCCGUUAGGCCGAA IGCAGCUU 5615
144 AGCUGCCC C CAGCAGGG 133 CCCUGCUG CUGAUGAGGCCGUUAGGCCGAA IGGCAGCU 5616
145 GCUGCCCC C AGCAGGGC 134 GCCCUGCU CUGAUGAGGCCGUUAGGCCGAA IGGGCAGC 5617
146 CUGCCCCC A GCAGGGCC 135 GGCCCUGC CUGAUGAGGCCGUUAGGCCGAA IGGGGCAG 5618
149 CCCCCAGC A GGGCCUGC 136 GCAGGCCC CUGAUGAGGCCGUUAGGCCGAA ICUGGGGG 5619
154 AGCAGGGC C UGCAGGCU 137 AGCCUGCA CUGAUGAGGCCGUUAGGCCGAA ICCCUGCU 5620
155 GCAGGGCC U GCAGGCUG 138 CAGCCUGC CUGAUGAGGCCGUUAGGCCGAA IGCCCUGC 5621
158 GGGCCUGC A GGCUGUGC 139 GCACAGCC CUGAUGAGGCCGUUAGGCCGAA ICAGGCCC 5622
162 CUGCAGGC U GUGCCCGU 140 ACGGGCAC CUGAUGAGGCCGUUAGGCCGAA ICCUGCAG 5623
167 GGCUGUGC C CGUGGGCA 141 UGCCCACG CUGAUGAGGCCGUUAGGCCGAA ICACAGCC 5624
168 GCUGUGCC C GUGGGCAU 142 AUGCCCAC CUGAUGAGGCCGUUAGGCCGAA IGCACAGC 5625
175 CCGUGGGC A UCCCUGCU 143 AGCAGGGA CUGAUGAGGCCGUUAGGCCGAA ICCCACGG 5626
178 UGGGCAUC C CUGCUGCC 144 GGCAGCAG CUGAUGAGGCCGUUAGGCCGAA IAUGCCCA 5627
179 GGGCAUCC C UGCUGCCA 145 UGGCAGCA CUGAUGAGGCCGUUAGGCCGAA IGAUGCCC 5628
180 GGCAUCCC U GCUGCCAG 146 CUGGCAGC CUGAUGAGGCCGUUAGGCCGAA IGGAUGCC 5629 183 AUCCCUGC U GCCAGCCA 147 UGGCUGGC CUGAUGAGGCCGUUAGGCCGAA ICAGGGAU 5630
186 CCUGCUGC C AGCCAGCG 148 CGCUGGCU CUGAUGAGGCCGUUAGGCCGAA ICAGCAGG 5631
187 CUGCUGCC A GCCAGCGC 149 GCGCUGGC CUGAUGAGGCCGUUAGGCCGAA IGCAGCAG 5632
190 CUGCCAGC C AGCGCAUC 150 GAUGCGCU CUGAUGAGGCCGUUAGGCCGAA ICUGGCAG 5633
191 UGCCAGCC A GCGCAUCU 151 AGAUGCGC CUGAUGAGGCCGUUAGGCCGAA IGCUGGCA 5634
196 GCCAGCGC A UCUUCCUG 152 CAGGAAGA CUGAUGAGGCCGUUAGGCCGAA ICGCUGGC 5635
199 AGCGCAUC U UCCUGCAC 153 GUGCAGGA CUGAUGAGGCCGUUAGGCCGAA IAUGCGCU 5636
202 GCAUCUUC C UGCACGGC 154 GCCGUGCA CUGAUGAGGCCGUUAGGCCGAA IAAGAUGC 5637
203 CAUCUUCC U GCACGGCA 155 UGCCGUGC CUGAUGAGGCCGUUAGGCCGAA IGAAGAUG 5638
206 CUUCCUGC A CGGCAACC 156 GGUUGCCG CUGAUGAGGCCGUUAGGCCGAA ICAGGAAG 5639
569 CUUCCUGC A CGGCAACC 156 GGUUGCCG CUGAUGAGGCCGUUAGGCCGAA ICAGGAAG 5639
211 UGCACGGC A ACCGCAUC 157 GAUGCGGU CUGAUGAGGCCGUUAGGCCGAA ICCGUGCA 5640
574 UGCACGGC A ACCGCAUC 157 GAUGCGGU CUGAUGAGGCCGUUAGGCCGAA ICCGUGCA 5640
214 ACGGCAAC C GCAUCUCG 158 CGAGAUGC CUGAUGAGGCCGUUAGGCCGAA IUUGCCGU 5641
217 GCAACCGC A UCUCGCAU 159 AUGCGAGA CUGAUGAGGCCGUUAGGCCGAA ICGGUUGC 5642
220 ACCGCAUC U CGCAUGUG 160 CACAUGCG CUGAUGAGGCCGUUAGGCCGAA IAUGCGGU 5643
22 CAUCUCGC A UGUGCCAG 161 CUGGCACA CUGAUGAGGCCGUUAGGCCGAA ICGAGAUG 5644
230 GCAUGUGC C AGCUGCCA 162 UGGCAGCU CUGAUGAGGCCGUUAGGCCGAA ICACAUGC 5645
231 CAUGUGCC A GCUGCCAG 163 CUGGCAGC CUGAUGAGGCCGUUAGGCCGAA IGCACAUG 5646
23 GUGCCAGC U GCCAGCUU 164 AAGCUGGC CUGAUGAGGCCGUUAGGCCGAA ICUGGCAC 5647
237 CCAGCUGC C AGCUUCCG 165 CGGAAGCU CUGAUGAGGCCGUUAGGCCGAA ICAGCUGG 5648
238 CAGCUGCC A GCUUCCGU 166 ACGGAAGC CUGAUGAGGCCGUUAGGCCGAA IGCAGCUG 5649
241 CUGCCAGC U UCCGUGCC 167 GGCACGGA CUGAUGAGGCCGUUAGGCCGAA ICUGGCAG 5650
244 CCAGCUUC C GUGCCUGC 168 GCAGGCAC CUGAUGAGGCCGUUAGGCCGAA IAAGCUGG 5651
249 UUCCGUGC C UGCCGCAA 169 UUGCGGCA CUGAUGAGGCCGUUAGGCCGAA ICACGGAA 5652
250 UCCGUGCC U GCCGCAAC 170 GUUGCGGC CUGAUGAGGCCGUUAGGCCGAA IGCACGGA 5653
253 GUGCCUGC C GCAACCUC 171 GAGGUUGC CUGAUGAGGCCGUUAGGCCGAA ICAGGCAC 5654
256 CCUGCCGC A ACCUCACC 172 GGUGAGGU CUGAUGAGGCCGUUAGGCCGAA ICGGCAGG 5655
259 GCCGCAAC C UCACCAUC 173 GAUGGUGA CUGAUGAGGCCGUUAGGCCGAA IUUGCGGC 5656
260 CCGCAACC U CACCAUCC 174 GGAUGGUG CUGAUGAGGCCGUUAGGCCGAA IGUUGCGG 5657
262 GCAACCUC A CCAUCCUG 175 CAGGAUGG CUGAUGAGGCCGUUAGGCCGAA IAGGUUGC 5658
26 AACCUCAC C AUCCUGUG 176 CACAGGAU CUGAUGAGGCCGUUAGGCCGAA IUGAGGUU 5659
265 ACCUCACC A UCCUGUGG 177 CCACAGGA CUGAUGAGGCCGUUAGGCCGAA IGUGAGGU 5660
268 UCACCAUC C UGUGGCUG 178 CAGCCACA CUGAUGAGGCCGUUAGGCCGAA IAUGGUGA 5661
269 CACCAUCC U GUGGCUGC 179 GCAGCCAC CUGAUGAGGCCGUUAGGCCGAA IGAUGGUG 5662
275 CCUGUGGC U GCACUCGA 180 UCGAGUGC CUGAUGAGGCCGUUAGGCCGAA ICCACAGG 5663
278 GUGGCUGC A CUCGAAUG 181 CAUUCGAG CUGAUGAGGCCGUUAGGCCGAA ICAGCCAC 5664
280 GGCUGCAC U CGAAUGUG 182 CACAUUCG CUGAUGAGGCCGUUAGGCCGAA IUGCAGCC 5665
290 GAAUGUGC U GGCCCGAA 183 UUCGGGCC CUGAUGAGGCCGUUAGGCCGAA ICACAUUC 5666
294 GUGCUGGC C CGAAUUGA 184 UCAAUUCG CUGAUGAGGCCGUUAGGCCGAA ICCAGCAC 5667
295 UGCUGGCC C GAAUUGAU 185 AUCAAUUC CUGAUGAGGCCGUUAGGCCGAA IGCCAGCA 5668
309 GAUGCGGC U GCCUUCAC 186 GUGAAGGC CUGAUGAGGCCGUUAGGCCGAA ICCGCAUC 5669
312 GCGGCUGC C UUCACUGG 187 CCAGUGAA CUGAUGAGGCCGUUAGGCCGAA ICAGCCGC 5670
313 CGGCUGCC U UCACUGGC 188 GCCAGUGA CUGAUGAGGCCGUUAGGCCGAA IGCAGCCG 5671
316 CUGCCUUC A CUGGCCUG 189 CAGGCCAG CUGAUGAGGCCGUUAGGCCGAA IAAGGCAG 5672
318 GCCUUCAC U GGCCUGGC 190 GCCAGGCC CUGAUGAGGCCGUUAGGCCGAA IUGAAGGC 5673
322 UCACUGGC C UGGCCCUC 191 GAGGGCCA CUGAUGAGGCCGUUAGGCCGAA ICCAGUGA 5674
323 CACUGGCC U GGCCCUCC 192 GGAGGGCC CUGAUGAGGCCGUUAGGCCGAA IGCCAGUG 5675
327 GGCCUGGC C CUCCUGGA 193 UCCAGGAG CUGAUGAGGCCGUUAGGCCGAA ICCAGGCC 5676
328 GCCUGGCC C UCCUGGAG 194 CUCCAGGA CUGAUGAGGCCGUUAGGCCGAA IGCCAGGC 5677
329 CCUGGCCC U CCUGGAGC 195 GCUCCAGG CUGAUGAGGCCGUUAGGCCGAA IGGCCAGG 5678 331 UGGCCCUC C UGGAGCAG 196 CUGCUCCA CUGAUGAGGCCGUUAGGCCGAA IAGGGCCA 5679
332 GGCCCUCC U GGAGCAGC 197 GCUGCUCC CUGAUGAGGCCGUUAGGCCGAA IGAGGGCC 5680
338 CCUGGAGC A GCUGGACC 198 GGUCCAGC CUGAUGAGGCCGUUAGGCCGAA ICUCCAGG 5681
341 GGAGCAGC U GGACCUCA 199 UGAGGUCC CUGAUGAGGCCGUUAGGCCGAA ICUGCUCC 5682
346 AGCUGGAC C UCAGCGAU 200 AUCGCUGA CUGAUGAGGCCGUUAGGCCGAA lUCCAGCU 5683
347 GCUGGACC U CAGCGAUA 201 UAUCGCUG CUGAUGAGGCCGUUAGGCCGAA IGUCCAGC 5684
349 UGGACCUC A GCGAUAAU 202 AUUAUCGC CUGAUGAGGCCGUUAGGCCGAA IAGGUCCA 5685
360 GAUAAUGC A CAGCUCCG 203 CGGAGCUG CUGAUGAGGCCGUUAGGCCGAA ICAUUAUC 5686
362 UAAUGCAC A GCUCCGGU 204 ACCGGAGC CUGAUGAGGCCGUUAGGCCGAA lUGCAUUA 5687
365 UGCACAGC U CCGGUCUG 205 CAGACCGG CUGAUGAGGCCGUUAGGCCGAA ICUGUGCA 5688
367 CACAGCUC C GGUCUGUG 206 CACAGACC CUGAUGAGGCCGUUAGGCCGAA IAGCUGUG 5689
372 CUCCGGUC U GUGGACCC 207 GGGUCCAC CUGAUGAGGCCGUUAGGCCGAA IACCGGAG 5690
379 CUGUGGAC C CUGCCACA 208 UGUGGCAG CUGAUGAGGCCGUUAGGCCGAA IUCCACAG 5691
380 UGUGGACC C UGCCACAU 209 AUGUGGCA CUGAUGAGGCCGUUAGGCCGAA IGUCCACA 5692
381 GUGGACCC U GCCACAUU 210 AAUGUGGC CUGAUGAGGCCGUUAGGCCGAA IGGUCCAC 5693
384 GACCCUGC C ACAUUCCA 211 UGGAAUGU CUGAUGAGGCCGUUAGGCCGAA ICAGGGUC 5694
385 ACCCUGCC A CAUUCCAC 212 GUGGAAUG CUGAUGAGGCCGUUAGGCCGAA IGCAGGGU 5695
387 CCUGCCAC A UUCCACGG 213 CCGUGGAA CUGAUGAGGCCGUUAGGCCGAA IUGGCAGG 5696
391 CCACAUUC C ACGGCCUG 214 CAGGCCGU CUGAUGAGGCCGUUAGGCCGAA IAAUGUGG 5697
392 CACAUUCC A CGGCCUGG 215 CCAGGCCG CUGAUGAGGCCGUUAGGCCGAA IGAAUGUG 5698
397 UCCACGGC C UGGGCCGC 216 GCGGCCCA CUGAUGAGGCCGUUAGGCCGAA ICCGUGGA 5699
398 CCACGGCC U GGGCCGCC 217 GGCGGCCC CUGAUGAGGCCGUUAGGCCGAA IGCCGUGG 5700
403 GCCUGGGC C GCCUACAC 218 GUGUAGGC CUGAUGAGGCCGUUAGGCCGAA ICCCAGGC 5701
406 UGGGCCGC C UACACACG 219 CGUGUGUA CUGAUGAGGCCGUUAGGCCGAA ICGGCCCA 5702
407 GGGCCGCC U ACACACGC 220 GCGUGUGU CUGAUGAGGCCGUUAGGCCGAA IGCGGCCC 5703
410 CCGCCUAC A CACGCUGC 221 GCAGCGUG CUGAUGAGGCCGUUAGGCCGAA IUAGGCGG 5704
412 GCCUACAC A CGCUGCAC 222 GUGCAGCG CUGAUGAGGCCGUUAGGCCGAA IUGUAGGC 5705
416 ACACACGC U GCACCUGG 223 CCAGGUGC CUGAUGAGGCCGUUAGGCCGAA ICGUGUGU 5706
419 CACGCUGC A CCUGGACC 224 GGUCCAGG CUGAUGAGGCCGUUAGGCCGAA ICAGCGUG 5707
421 CGCUGCAC C UGGACCGC 225 GCGGUCCA CUGAUGAGGCCGUUAGGCCGAA IUGCAGCG 5708
422 GCUGCACC U GGACCGCU 226 AGCGGUCC CUGAUGAGGCCGUUAGGCCGAA IGUGCAGC 5709
427 ACCUGGAC C GCUGCGGC 227 GCCGCAGC CUGAUGAGGCCGUUAGGCCGAA IUCCAGGU 5710
430 UGGACCGC U GCGGCCUG 228 CAGGCCGC CUGAUGAGGCCGUUAGGCCGAA ICGGUCCA 5711
436 GCUGCGGC C UGCAGGAG 229 CUCCUGCA CUGAUGAGGCCGUUAGGCCGAA ICCGCAGC 5712
437 CUGCGGCC U GCAGGAGC 230 GCUCCUGC CUGAUGAGGCCGUUAGGCCGAA IGCCGCAG 5713
440 CGGCCUGC A GGAGCUGG 231 CCAGCUCC CUGAUGAGGCCGUUAGGCCGAA ICAGGCCG 5714
446 GCAGGAGC U GGGCCCGG 232 CCGGGCCC CUGAUGAGGCCGUUAGGCCGAA ICUCCUGC 5715
451 AGCUGGGC C CGGGGCUG 233 CAGCCCCG CUGAUGAGGCCGUUAGGCCGAA ICCCAGCU 5716
452 GCUGGGCC C GGGGCUGU 234 ACAGCCCC CUGAUGAGGCCGUUAGGCCGAA IGCCCAGC 5717
458 CCCGGGGC U GUUCCGCG 235 CGCGGAAC CUGAUGAGGCCGUUAGGCCGAA ICCCCGGG 5718
463 GGCUGUUC C GCGGCCUG 236 CAGGCCGC CUGAUGAGGCCGUUAGGCCGAA IAACAGCC 5719
469 UCCGCGGC C UGGCUGCC 237 GGCAGCCA CUGAUGAGGCCGUUAGGCCGAA ICCGCGGA 5720
470 CCGCGGCC U GGCUGCCC 238 GGGCAGCC CUGAUGAGGCCGUUAGGCCGAA IGCCGCGG 5721
474 GGCCUGGC U GCCCUGCA 239 UGCAGGGC CUGAUGAGGCCGUUAGGCCGAA ICCAGGCC 5722
477 CUGGCUGC C CUGCAGUA 240 UACUGCAG CUGAUGAGGCCGUUAGGCCGAA ICAGCCAG 5723
478 UGGCUGCC C UGCAGUAC 241 GUACUGCA CUGAUGAGGCCGUUAGGCCGAA IGCAGCCA 5724
479 GGCUGCCC U GCAGUACC 242 GGUACUGC CUGAUGAGGCCGUUAGGCCGAA IGGCAGCC 5725
482 UGCCCUGC A GUACCUCU 243 AGAGGUAC CUGAUGAGGCCGUUAGGCCGAA ICAGGGCA 5726
487 UGCAGUAC C UCUACCUG 244 CAGGUAGA CUGAUGAGGCCGUUAGGCCGAA IUACUGCA 5727
488 GCAGUACC U CUACCUGC 245 GCAGGUAG CUGAUGAGGCCGUUAGGCCGAA IGUACUGC 5728
490 AGUACCUC U ACCUGCAG 246 CUGCAGGU CUGAUGAGGCCGUUAGGCCGAA IAGGUACU 5729 493 ACCUCUAC C UGCAGGAC 247 GUCCUGCA CUGAUGAGGCCGUUAGGCCGAA IUAGAGGU 5730
494 CCUCUACC U GCAGGACA 248 UGUCCUGC CUGAUGAGGCCGUUAGGCCGAA IGUAGAGG 5731
497 CUACCUGC A GGACAACG 249 CGUUGUCC CUGAUGAGGCCGUUAGGCCGAA ICAGGUAG 5732
502 UGCAGGAC A ACGCGCUG 250 CAGCGCGU CUGAUGAGGCCGUUAGGCCGAA IUCCUGCA 5733
509 CAACGCGC U GCAGGCAC 251 GUGCCUGC CUGAUGAGGCCGUUAGGCCGAA ICGCGUUG 5734
512 CGCGCUGC A GGCACUGC 252 GCAGUGCC CUGAUGAGGCCGUUAGGCCGAA ICAGCGCG 5735
516 CUGCAGGC A CUGCCUGA 253 UCAGGCAG CUGAUGAGGCCGUUAGGCCGAA ICCUGCAG 5736
518 GCAGGCAC U GCCUGAUG 254 CAUCAGGC CUGAUGAGGCCGUUAGGCCGAA IUGCCUGC 5737
521 GGCACUGC C UGAUGACA 255 UGUCAUCA CUGAUGAGGCCGUUAGGCCGAA ICAGUGCC 5738
522 GCACUGCC U GAUGACAC 256 GUGUCAUC CUGAUGAGGCCGUUAGGCCGAA IGCAGUGC 5739
529 CUGAUGAC A CCUUCCGC 257 GCGGAAGG CUGAUGAGGCCGUUAGGCCGAA IUCAUCAG 5740
531 GAUGACAC C UUCCGCGA 258 UCGCGGAA CUGAUGAGGCCGUUAGGCCGAA IUGUCAUC 5741
532 AUGACACC U UCCGCGAC 259 GUCGCGGA CUGAUGAGGCCGUUAGGCCGAA IGUGUCAU 5742
535 ACACCUUC C GCGACCUG 260 CAGGUCGC CUGAUGAGGCCGUUAGGCCGAA IAAGGUGU 5743
541 UCCGCGAC C UGGGCAAC 261 GUUGCCCA CUGAUGAGGCCGUUAGGCCGAA lUCGCGGA 5744
542 CCGCGACC U GGGCAACC 262 GGUUGCCC CUGAUGAGGCCGUUAGGCCGAA IGUCGCGG 5745
547 ACCUGGGC A ACCUCACA 263 UGUGAGGU CUGAUGAGGCCGUUAGGCCGAA ICCCAGGU 5746
550 UGGGCAAC C UCACACAC 264 GUGUGUGA CUGAUGAGGCCGUUAGGCCGAA IUUGCCCA 5747
551 GGGCAACC U CACACACC 265 GGUGUGUG CUGAUGAGGCCGUUAGGCCGAA IGUUGCCC 5748
553 GCAACCUC A CACACCUC 266 GAGGUGUG CUGAUGAGGCCGUUAGGCCGAA IAGGUUGC 5749
555 AACCUCAC A CACCUCUU 267 AAGAGGUG CUGAUGAGGCCGUUAGGCCGAA IUGAGGUU 5750
557 CCUCACAC A CCUCUUCC 268 GGAAGAGG CUGAUGAGGCCGUUAGGCCGAA IUGUGAGG 5751
559 UCACACAC C UCUUCCUG 269 CAGGAAGA CUGAUGAGGCCGUUAGGCCGAA IUGUGUGA 5752
560 CACACACC U CUUCCUGC 270 GCAGGAAG CUGAUGAGGCCGUUAGGCCGAA IGUGUGUG 5753
562 CACACCUC U UCCUGCAC 271 GUGCAGGA CUGAUGAGGCCGUUAGGCCGAA IAGGUGUG 575
565 ACCUCUUC C UGCACGGC 272 GCCGUGCA CUGAUGAGGCCGUUAGGCCGAA IAAGAGGU 5755
566 CCUCUUCC U GCACGGCA 273 UGCCGUGC CUGAUGAGGCCGUUAGGCCGAA IGAAGAGG 5756
577 ACGGCAAC C GCAUCUCC 274 GGAGAUGC CUGAUGAGGCCGUUAGGCCGAA IUUGCCGU 5757
580 GCAACCGC A UCUCCAGC 275 GCUGGAGA CUGAUGAGGCCGUUAGGCCGAA ICGGUUGC 5758
583 ACCGCAUC U CCAGCGUG 276 CACGCUGG CUGAUGAGGCCGUUAGGCCGAA IAUGCGGU 5759
585 CGCAUCUC C AGCGUGCC 277 GGCACGCU CUGAUGAGGCCGUUAGGCCGAA IAGAUGCG 5760
586 GCAUCUCC A GCGUGCCC 278 GGGCACGC CUGAUGAGGCCGUUAGGCCGAA IGAGAUGC 5761
593 CAGCGUGC C CGAGCGCG 279 CGCGCUCG CUGAUGAGGCCGUUAGGCCGAA ICACGCUG 5762
594 AGCGUGCC C GAGCGCGC 280 GCGCGCUC CUGAUGAGGCCGUUAGGCCGAA IGCACGCU 5763
603 GAGCGCGC C UUCCGUGG 281 CCACGGAA CUGAUGAGGCCGUUAGGCCGAA ICGCGCUC 5764
604 AGCGCGCC U UCCGUGGG 282 CCCACGGA CUGAUGAGGCCGUUAGGCCGAA IGCGCGCU 5765
607 GCGCCUUC C GUGGGCUG 283 CAGCCCAC CUGAUGAGGCCGUUAGGCCGAA IAAGGCGC 5766
614 CCGUGGGC U GCACAGCC 284 GGCUGUGC CUGAUGAGGCCGUUAGGCCGAA ICCCACGG 5767
617 UGGGCUGC A CAGCCUCG 285 CGAGGCUG CUGAUGAGGCCGUUAGGCCGAA ICAGCCCA 5768
619 GGCUGCAC A GCCUCGAC 286 GUCGAGGC CUGAUGAGGCCGUUAGGCCGAA IUGCAGCC 5769
622 UGCACAGC C UCGACCGU 287 ACGGUCGA CUGAUGAGGCCGUUAGGCCGAA ICUGUGCA 5770
623 GCACAGCC U CGACCGUC 288 GACGGUCG CUGAUGAGGCCGUUAGGCCGAA IGCUGUGC 5771
628 GCCUCGAC C GUCUCCUA 289 UAGGAGAC CUGAUGAGGCCGUUAGGCCGAA IUCGAGGC 5772
632 CGACCGUC U CCUACUGC 290 GCAGUAGG CUGAUGAGGCCGUUAGGCCGAA IACGGUCG 5773
634 ACCGUCUC C UACUGCAC 291 GUGCAGUA CUGAUGAGGCCGUUAGGCCGAA IAGACGGU 5774
635 CCGUCUCC U ACUGCACC 292 GGUGCAGU CUGAUGAGGCCGUUAGGCCGAA IGAGACGG 5775
638 UCUCCUAC U GCACCAGA 293 UCUGGUGC CUGAUGAGGCCGUUAGGCCGAA lUAGGAGA 5776
641 CCUACUGC A CCAGAACC 294 GGUUCUGG CUGAUGAGGCCGUUAGGCCGAA ICAGUAGG 5777
643 UACUGCAC C AGAACCGC 295 GCGGUUCU CUGAUGAGGCCGUUAGGCCGAA IUGCAGUA 5778
64 ACUGCACC A GAACCGCG 296 CGCGGUUC CUGAUGAGGCCGUUAGGCCGAA IGUGCAGU 5779
649 ACCAGAAC C GCGUGGCC 297 GGCCACGC CUGAUGAGGCCGUUAGGCCGAA IUUCUGGU 5780 657 CGCGUGGC C CAUGUGCA 298 UGCACAUG CUGAUGAGGCCGUUAGGCCGAA ICCACGCG 5781
658 GCGUGGCC C AUGUGCAC 299 GUGCACAU CUGAUGAGGCCGUUAGGCCGAA IGCCACGC 5782
659 CGUGGCCC A UGUGCACC 300 GGUGCACA CUGAUGAGGCCGUUAGGCCGAA IGGCCACG 5783
665 CCAUGUGC A CCCGCAUG 301 CAUGCGGG CUGAUGAGGCCGUUAGGCCGAA ICACAUGG 5784
667 AUGUGCAC C CGCAUGCC 302 GGCAUGCG CUGAUGAGGCCGUUAGGCCGAA IUGCACAU 5785
668 UGUGCACC C GCAUGCCU 303 AGGCAUGC CUGAUGAGGCCGUUAGGCCGAA IGUGCACA 5786
671 GCACCCGC A UGCCUUCC 304 GGAAGGCA CUGAUGAGGCCGUUAGGCCGAA ICGGGUGC 5787
675 CCGCAUGC C UUCCGUGA 305 UCACGGAA CUGAUGAGGCCGUUAGGCCGAA ICAUGCGG 5788
676 CGCAUGCC U UCCGUGAC 306 GUCACGGA CUGAUGAGGCCGUUAGGCCGAA IGCAUGCG 5789
679 AUGCCUUC C GUGACCUU 307 AAGGUCAC CUGAUGAGGCCGUUAGGCCGAA IAAGGCAU 5790
685 UCCGUGAC C UUGGCCGC 308 GCGGCCAA CUGAUGAGGCCGUUAGGCCGAA IUCACGGA 5791
686 CCGUGACC U UGGCCGCC 309 GGCGGCCA CUGAUGAGGCCGUUAGGCCGAA IGUCACGG 5792
691 ACCUUGGC C GCCUCAUG 310 CAUGAGGC CUGAUGAGGCCGUUAGGCCGAA ICCAAGGU 5793
694 UUGGCCGC C UCAUGACA 311 UGUCAUGA CUGAUGAGGCCGUUAGGCCGAA ICGGCCAA 5794
695 UGGCCGCC U CAUGACAC 312 GUGUCAUG CUGAUGAGGCCGUUAGGCCGAA IGCGGCCA 5795
697 GCCGCCUC A UGACACUC 313 GAGUGUCA CUGAUGAGGCCGUUAGGCCGAA IAGGCGGC 5796
702 CUCAUGAC A CUCUAUCU 314 AGAUAGAG CUGAUGAGGCCGUUAGGCCGAA lUCAUGAG 5797
704 CAUGACAC U CUAUCUGU 315 ACAGAUAG CUGAUGAGGCCGUUAGGCCGAA IUGUCAUG 5798
706 UGACACUC U AUCUGUUU 316 AAACAGAU CUGAUGAGGCCGUUAGGCCGAA IAGUGUCA 5799
710 ACUCUAUC U GUUUGCCA 317 UGGCAAAC CUGAUGAGGCCGUUAGGCCGAA IAUAGAGU 5800
717 CUGUUUGC C AACAAUCU 318 AGAUUGUU CUGAUGAGGCCGUUAGGCCGAA ICAAACAG 5801
718 UGUUUGCC A ACAAUCUA 319 UAGAUUGU CUGAUGAGGCCGUUAGGCCGAA IGCAAACA 5802
721 UUGCCAAC A AUCUAUCA 320 UGAUAGAU CUGAUGAGGCCGUUAGGCCGAA IUUGGCAA 5803
725 CAACAAUC U AUCAGCGC 321 GCGCUGAU CUGAUGAGGCCGUUAGGCCGAA IAUUGUUG 5804
729 AAUCUAUC A GCGCUGCC 322 GGCAGCGC CUGAUGAGGCCGUUAGGCCGAA IAUAGAUU 5805
734 AUCAGCGC U GCCCACUG 323 CAGUGGGC CUGAUGAGGCCGUUAGGCCGAA ICGCUGAU 5806
737 AGCGCUGC C CACUGAGG 324 CCUCAGUG CUGAUGAGGCCGUUAGGCCGAA ICAGCGCU 5807
738 GCGCUGCC C ACUGAGGC 325 GCCUCAGU CUGAUGAGGCCGUUAGGCCGAA IGCAGCGC 5808
739 CGCUGCCC A CUGAGGCC 326 GGCCUCAG CUGAUGAGGCCGUUAGGCCGAA IGGCAGCG 5809
741 CUGCCCAC U GAGGCCCU 327 AGGGCCUC CUGAUGAGGCCGUUAGGCCGAA IUGGGCAG 5810
747 ACUGAGGC C CUGGCCCC 328 GGGGCCAG CUGAUGAGGCCGUUAGGCCGAA ICCUCAGU 5811
748 CUGAGGCC C UGGCCCCC 329 GGGGGCCA CUGAUGAGGCCGUUAGGCCGAA IGCCUCAG 5812
749 UGAGGCCC U GGCCCCCC 330 GGGGGGCC CUGAUGAGGCCGUUAGGCCGAA IGGCCUCA 5813
753 GCCCUGGC C CCCCUGCG 331 CGCAGGGG CUGAUGAGGCCGUUAGGCCGAA ICCAGGGC 5814
754 CCCUGGCC C CCCUGCGU 332 ACGCAGGG CUGAUGAGGCCGUUAGGCCGAA IGCCAGGG 5815
755 CCUGGCCC C CCUGCGUG 333 CACGCAGG CUGAUGAGGCCGUUAGGCCGAA IGGCCAGG 5816
756 CUGGCCCC C CUGCGUGC 334 GCACGCAG CUGAUGAGGCCGUUAGGCCGAA IGGGCCAG 5817
757 UGGCCCCC C UGCGUGCC 335 GGCACGCA CUGAUGAGGCCGUUAGGCCGAA IGGGGCCA 5818
758 GGCCCCCC U GCGUGCCC 336 GGGCACGC CUGAUGAGGCCGUUAGGCCGAA IGGGGGCC 5819
765 CUGCGUGC C CUGCAGUA 337 UACUGCAG CUGAUGAGGCCGUUAGGCCGAA ICACGCAG 5820
766 UGCGUGCC C UGCAGUAC 338 GUACUGCA CUGAUGAGGCCGUUAGGCCGAA IGCACGCA 5821
767 GCGUGCCC U GCAGUACC 339 GGUACUGC CUGAUGAGGCCGUUAGGCCGAA IGGCACGC 5822
770 UGCCCUGC A GUACCUGA 340 UCAGGUAC CUGAUGAGGCCGUUAGGCCGAA ICAGGGCA 5823
775 UGCAGUAC C UGAGGCUC 341 GAGCCUCA CUGAUGAGGCCGUUAGGCCGAA IUACUGCA 5824
776 GCAGUACC U GAGGCUCA 342 UGAGCCUC CUGAUGAGGCCGUUAGGCCGAA IGUACUGC 5825
782 CCUGAGGC U CAACGACA 343 UGUCGUUG CUGAUGAGGCCGUUAGGCCGAA ICCUCAGG 5826
784 UGAGGCUC A ACGACAAC 344 GUUGUCGU CUGAUGAGGCCGUUAGGCCGAA IAGCCUCA 5827
790 UCAACGAC A ACCCCUGG 345 CCAGGGGU CUGAUGAGGCCGUUAGGCCGAA IUCGUUGA 5828
793 ACGACAAC C CCUGGGUG 346 CACCCAGG CUGAUGAGGCCGUUAGGCCGAA IUUGUCGU 5829
794 CGACAACC C CUGGGUGU 347 ACACCCAG CUGAUGAGGCCGUUAGGCCGAA IGUUGUCG 5830
795 GACAACCC C UGGGUGUG 348 CACACCCA CUGAUGAGGCCGUUAGGCCGAA IGGUUGUC 5831 796 ACAACCCC U GGGUGUGU 349 ACACACCC CUGAUGAGGCCGUUAGGCCGAA IGGGUUGU 5832
808 UGUGUGAC U GCCGGGCA 350 UGCCCGGC CUGAUGAGGCCGUUAGGCCGAA IUCACACA 5833
811 GUGACUGC C GGGCACGC 351 GCGUGCCC CUGAUGAGGCCGUUAGGCCGAA ICAGUCAC 5834
816 UGCCGGGC A CGCCCACU 352 AGUGGGCG CUGAUGAGGCCGUUAGGCCGAA ICCCGGCA 5835
820 GGGCACGC C CACUCUGG 353 CCAGAGUG CUGAUGAGGCCGUUAGGCCGAA ICGUGCCC 5836
821 GGCACGCC C ACUCUGGG 354 CCCAGAGU CUGAUGAGGCCGUUAGGCCGAA IGCGUGCC 5837
822 GCACGCCC A CUCUGGGC 355 GCCCAGAG CUGAUGAGGCCGUUAGGCCGAA IGGCGUGC 5838
824 ACGCCCAC U CUGGGCCU 356 AGGCCCAG CUGAUGAGGCCGUUAGGCCGAA lUGGGCGU 5839
826 GCCCACUC U GGGCCUGG 357 CCAGGCCC CUGAUGAGGCCGUUAGGCCGAA IAGUGGGC 5840
831 CUCUGGGC C UGGCUGCA 358 UGCAGCCA CUGAUGAGGCCGUUAGGCCGAA ICCCAGAG 5841
832 UCUGGGCC U GGCUGCAG 359 CUGCAGCC CUGAUGAGGCCGUUAGGCCGAA IGCCCAGA 5842
836 GGCCUGGC U GCAGAAGU 360 ACUUCUGC CUGAUGAGGCCGUUAGGCCGAA ICCAGGCC 5843
839 CUGGCUGC A GAAGUUCC 361 GGAACUUC CUGAUGAGGCCGUUAGGCCGAA ICAGCCAG 5844
847 AGAAGUUC C GCGGCUCC 362 GGAGCCGC CUGAUGAGGCCGUUAGGCCGAA IAACUUCU 5845
853 UCCGCGGC U CCUCCUCC 363 GGAGGAGG CUGAUGAGGCCGUUAGGCCGAA ICCGCGGA 5846
855 CGCGGCUC C UCCUCCGA 364 UCGGAGGA CUGAUGAGGCCGUUAGGCCGAA IAGCCGCG 5847
856 GCGGCUCC U CCUCCGAG 365 CUCGGAGG CUGAUGAGGCCGUUAGGCCGAA IGAGCCGC 5848
858 GGCUCCUC C UCCGAGGU 366 ACCUCGGA CUGAUGAGGCCGUUAGGCCGAA IAGGAGCC 5849
859 GCUCCUCC U CCGAGGUG 367 CACCUCGG CUGAUGAGGCCGUUAGGCCGAA IGAGGAGC 5850
861 UCCUCCUC C GAGGUGCC 368 GGCACCUC CUGAUGAGGCCGUUAGGCCGAA IAGGAGGA 5851
869 CGAGGUGC C CUGCAGCC 369 GGCUGCAG CUGAUGAGGCCGUUAGGCCGAA ICACCUCG 5852
870 GAGGUGCC C UGCAGCCU 370 AGGCUGCA CUGAUGAGGCCGUUAGGCCGAA IGCACCUC 5853
871 AGGUGCCC u GCAGCCUC 371 GAGGCUGC CUGAUGAGGCCGUUAGGCCGAA IGGCACCU 5854
874 UGCCCUGC A GCCUCCCG 372 CGGGAGGC CUGAUGAGGCCGUUAGGCCGAA ICAGGGCA 5855
877 CCUGCAGC C UCCCGCAA 373 UUGCGGGA CUGAUGAGGCCGUUAGGCCGAA ICUGCAGG 5856
878 CUGCAGCC U CCCGCAAC 374 GUUGCGGG CUGAUGAGGCCGUUAGGCCGAA IGCUGCAG 5857
880 GCAGCCUC C CGCAACGC 375 GCGUUGCG CUGAUGAGGCCGUUAGGCCGAA IAGGCUGC 5858
881 CAGCCUCC C GCAACGCC 376 GGCGUUGC CUGAUGAGGCCGUUAGGCCGAA IGAGGCUG 5859
884 CCUCCCGC A ACGCCUGG 377 CCAGGCGU CUGAUGAGGCCGUUAGGCCGAA ICGGGAGG 5860
889 CGCAACGC C UGGCUGGC 378 GCCAGCCA CUGAUGAGGCCGUUAGGCCGAA ICGUUGCG 5861
890 GCAACGCC U GGCUGGCC 379 GGCCAGCC CUGAUGAGGCCGUUAGGCCGAA IGCGUUGC 5862
894 CGCCUGGC U GGCCGUGA 380 UCACGGCC CUGAUGAGGCCGUUAGGCCGAA ICCAGGCG 5863
898 UGGCUGGC C GUGACCUC 381 GAGGUCAC CUGAUGAGGCCGUUAGGCCGAA ICCAGCCA 5864
904 GCCGUGAC C UCAAACGC 382 GCGUUUGA CUGAUGAGGCCGUUAGGCCGAA IUCACGGC 5865
905 CCGUGACC U CAAACGCC 383 GGCGUUUG CUGAUGAGGCCGUUAGGCCGAA IGUCACGG 5866
907 GUGACCUC A AACGCCUA 384 UAGGCGUU CUGAUGAGGCCGUUAGGCCGAA IAGGUCAC 5867
913 UCAAACGC C UAGCUGCC 385 GGCAGCUA CUGAUGAGGCCGUUAGGCCGAA ICGUUUGA 5868
914 CAAACGCC U AGCUGCCA 386 UGGCAGCU CUGAUGAGGCCGUUAGGCCGAA IGCGUUUG 5869
918 CGCCUAGC U GCCAAUGA 387 UCAUUGGC CUGAUGAGGCCGUUAGGCCGAA ICUAGGCG 5870
921 CUAGCUGC C AAUGACCU 388 AGGUCAUU CUGAUGAGGCCGUUAGGCCGAA ICAGCUAG 5871
922 UAGCUGCC A AUGACCUG 389 CAGGUCAU CUGAUGAGGCCGUUAGGCCGAA IGCAGCUA 5872
928 CCAAUGAC C UGCAGGGC 390 GCCCUGCA CUGAUGAGGCCGUUAGGCCGAA IUCAUUGG 5873
929 CAAUGACC U GCAGGGCU 391 AGCCCUGC CUGAUGAGGCCGUUAGGCCGAA IGUCAUUG 5874
932 UGACCUGC A GGGCUGCG 392 CGCAGCCC CUGAUGAGGCCGUUAGGCCGAA ICAGGUCA 5875
937 UGCAGGGC U GCGCUGUG 393 CACAGCGC CUGAUGAGGCCGUUAGGCCGAA ICCCUGCA 5876
942 GGCUGCGC U GUGGCCAC 394 GUGGCCAC CUGAUGAGGCCGUUAGGCCGAA ICGCAGCC 5877
948 GCUGUGGC c ACCGGCCC 395 GGGCCGGU CUGAUGAGGCCGUUAGGCCGAA ICCACAGC 5878
949 CUGUGGCC A CCGGCCCU 396 AGGGCCGG CUGAUGAGGCCGUUAGGCCGAA IGCCACAG 5879
951 GUGGCCAC c GGCCCUUA 397 UAAGGGCC CUGAUGAGGCCGUUAGGCCGAA IUGGCCAC 5880
955 CCACCGGC c CUUACCAU 398 AUGGUAAG CUGAUGAGGCCGUUAGGCCGAA ICCGGUGG 5881
956 CACCGGCC c UUACCAUC 399 GAUGGUAA CUGAUGAGGCCGUUAGGCCGAA IGCCGGUG 5882 957 ACCGGCCC U UACCAUCC 400 GGAUGGUA CUGAUGAGGCCGUUAGGCCGAA IGGCCGGU 5883
961 GCCCUUAC C AUCCCAUC 401 GAUGGGAU CUGAUGAGGCCGUUAGGCCGAA IUAAGGGC 5884
962 CCCUUACC A UCCCAUCU 402 AGAUGGGA CUGAUGAGGCCGUUAGGCCGAA IGUAAGGG 5885
965 UUACCAUC C CAUCUGGA 403 UCCAGAUG CUGAUGAGGCCGUUAGGCCGAA lAUGGUAA 5886
966 UACCAUCC C AUCUGGAC 404 GUCCAGAU CUGAUGAGGCCGUUAGGCCGAA IGAUGGUA 5887
967 ACCAUCCC A UCUGGACC 405 GGUCCAGA CUGAUGAGGCCGUUAGGCCGAA IGGAUGGU 5888
970 AUCCCAUC U GGACCGGC 406 GCCGGUCC CUGAUGAGGCCGUUAGGCCGAA IAUGGGAU 5889
975 AUCUGGAC C GGCAGGGC 407 GCCCUGCC CUGAUGAGGCCGUUAGGCCGAA IUCCAGAU 5890
979 GGACCGGC A GGGCCACC 08 GGUGGCCC CUGAUGAGGCCGUUAGGCCGAA ICCGGUCC 5891
984 GGCAGGGC C ACCGAUGA 409 UCAUCGGU CUGAUGAGGCCGUUAGGCCGAA ICCCUGCC 5892
985 GCAGGGCC A CCGAUGAG 410 CUCAUCGG CUGAUGAGGCCGUUAGGCCGAA IGCCCUGC 5893
987 AGGGCCAC C GAUGAGGA 411 UCCUCAUC CUGAUGAGGCCGUUAGGCCGAA IUGGCCCU 5894
998 UGAGGAGC C GCUGGGGC 412 GCCCCAGC CUGAUGAGGCCGUUAGGCCGAA ICUCCUCA 5895
1001 GGAGCCGC U GGGGCUUC 413 GAAGCCCC CUGAUGAGGCCGUUAGGCCGAA ICGGCUCC 5896
1007 GCUGGGGC U UCCCAAGU 414 ACUUGGGA CUGAUGAGGCCGUUAGGCCGAA ICCCCAGC 5897
1010 GGGGCUUC C CAAGUGCU 415 AGCACUUG CUGAUGAGGCCGUUAGGCCGAA IAAGCCCC 5898
1011 GGGCUUCC C AAGUGCUG 416 CAGCACUU CUGAUGAGGCCGUUAGGCCGAA IGAAGCCC 5899
1012 GGCUUCCC A AGUGCUGC 417 GCAGCACU CUGAUGAGGCCGUUAGGCCGAA IGGAAGCC 5900
1018 CCAAGUGC u GCCAGCCA 418 UGGCUGGC CUGAUGAGGCCGUUAGGCCGAA ICACUUGG 5901
1021 AGUGCUGC c AGCCAGAU 419 AUCUGGCU CUGAUGAGGCCGUUAGGCCGAA ICAGCACU 5902
1022 GUGCUGCC A GCCAGAUG 420 CAUCUGGC CUGAUGAGGCCGUUAGGCCGAA IGCAGCAC 5903
1025 CUGCCAGC C AGAUGCCG 421 CGGCAUCU CUGAUGAGGCCGUUAGGCCGAA ICUGGCAG 5904
1026 UGCCAGCC A GAUGCCGC 422 GCGGCAUC CUGAUGAGGCCGUUAGGCCGAA IGCUGGCA 5905
1032 CCAGAUGC C GCUGACAA 423 UUGUCAGC CUGAUGAGGCCGUUAGGCCGAA ICAUCUGG 5906
1035 GAUGCCGC U GACAAGGC 424 GCCUUGUC CUGAUGAGGCCGUUAGGCCGAA ICGGCAUC 5907
1039 CCGCUGAC A AGGCCUCA 425 UGAGGCCU CUGAUGAGGCCGUUAGGCCGAA IUCAGCGG 5908
1044 GACAAGGC C UCAGUACU 426 AGUACUGA CUGAUGAGGCCGUUAGGCCGAA ICCUUGUC 5909
1045 ACAAGGCC U CAGUACUG 427 CAGUACUG CUGAUGAGGCCGUUAGGCCGAA IGCCUUGU 5910
1047 AAGGCCUC A GUACUGGA 428 UCCAGUAC CUGAUGAGGCCGUUAGGCCGAA IAGGCCUU 5911
1052 CUCAGUAC U GGAGCCUG 429 CAGGCUCC CUGAUGAGGCCGUUAGGCCGAA IUACUGAG 5912
1058 ACUGGAGC C UGGAAGAC 430 GUCUUCCA CUGAUGAGGCCGUUAGGCCGAA ICUCCAGU 5913
1059 CUGGAGCC U GGAAGACC 431 GGUCUUCC CUGAUGAGGCCGUUAGGCCGAA IGCUCCAG 5914
1067 UGGAAGAC C AGCUUCGG 432 CCGAAGCU CUGAUGAGGCCGUUAGGCCGAA IUCUUCCA 5915
1068 GGAAGACC A GCUUCGGC 433 GCCGAAGC CUGAUGAGGCCGUUAGGCCGAA IGUCUUCC 5916
1071 AGACCAGC U UCGGCAGG 434 CCUGCCGA CUGAUGAGGCCGUUAGGCCGAA ICUGGUCU 5917
1077 GCUUCGGC A GGCAAUGC 435 GCAUUGCC CUGAUGAGGCCGUUAGGCCGAA ICCGAAGC 5918
1081 CGGCAGGC A AUGCGCUG 436 CAGCGCAU CUGAUGAGGCCGUUAGGCCGAA ICCUGCCG 5919
1088 CAAUGCGC U GAAGGGAC 437 GUCCCUUC CUGAUGAGGCCGUUAGGCCGAA ICGCAUUG 5920
1103 ACGCGUGC C GCCCGGUG 438 CACCGGGC CUGAUGAGGCCGUUAGGCCGAA ICACGCGU 5921
1106 CGUGCCGC C CGGUGACA 439 UGUCACCG CUGAUGAGGCCGUUAGGCCGAA ICGGCACG 5922
1107 GUGCCGCC C GGUGACAG 440 CUGUCACC CUGAUGAGGCCGUUAGGCCGAA IGCGGCAC 5923
1114 CCGGUGAC A GCCCGCCG 441 CGGCGGGC CUGAUGAGGCCGUUAGGCCGAA IUCACCGG 5924
1117 GUGACAGC C CGCCGGGC 442 GCCCGGCG CUGAUGAGGCCGUUAGGCCGAA ICUGUCAC 5925
1118 UGACAGCC C GCCGGGCA 443 UGCCCGGC CUGAUGAGGCCGUUAGGCCGAA IGCUGUCA 5926
1121 CAGCCCGC C GGGCAACG 444 CGUUGCCC CUGAUGAGGCCGUUAGGCCGAA ICGGGCUG 5927
1126 CGCCGGGC A ACGGCUCU 445 AGAGCCGU CUGAUGAGGCCGUUAGGCCGAA ICCCGGCG 5928
1132 GCAACGGC U CUGGCCCA 446 UGGGCCAG CUGAUGAGGCCGUUAGGCCGAA ICCGUUGC 5929
1134 AACGGCUC U GGCCCACG 447 CGUGGGCC CUGAUGAGGCCGUUAGGCCGAA IAGCCGUU 5930
1138 GCUCUGGC C CACGGCAC 448 GUGCCGUG CUGAUGAGGCCGUUAGGCCGAA ICCAGAGC 5931
1139 CUCUGGCC C ACGGCACA 449 UGUGCCGU CUGAUGAGGCCGUUAGGCCGAA IGCCAGAG 5932
1140 UCUGGCCC A CGGCACAU 450 AUGUGCCG CUGAUGAGGCCGUUAGGCCGAA IGGCCAGA 5933 1145 CCCACGGC A CAUCAAUG 451 CAUUGAUG CUGAUGAGGCCGUUAGGCCGAA ICCGUGGG 5934
1147 CACGGCAC A UCAAUGAC 452 GUCAUUGA CUGAUGAGGCCGUUAGGCCGAA IUGCCGUG 5935
1150 GGCACAUC A AUGACUCA 453 UGAGUCAU CUGAUGAGGCCGUUAGGCCGAA IAUGUGCC 5936
1156 UCAAUGAC U CACCCUUU 454 AAAGGGUG CUGAUGAGGCCGUUAGGCCGAA lUCAUUGA 5937
1158 AAUGACUC A CCCUUUGG 455 CCAAAGGG CUGAUGAGGCCGUUAGGCCGAA IAGUCAUU 5938
1160 UGACUCAC C CUUUGGGA 456 UCCCAAAG CUGAUGAGGCCGUUAGGCCGAA lUGAGUCA 5939
1161 GACUCACC C UUUGGGAC 457 GUCCCAAA CUGAUGAGGCCGUUAGGCCGAA IGUGAGUC 5940
1162 ACUCACCC U UUGGGACU 458 AGUCCCAA CUGAUGAGGCCGUUAGGCCGAA IGGUGAGU 5941
1170 UUUGGGAC U CUGCCUGG 459 CCAGGCAG CUGAUGAGGCCGUUAGGCCGAA IUCCCAAA 5942
1172 UGGGACUC U GCCUGGCU 460 AGCCAGGC CUGAUGAGGCCGUUAGGCCGAA IAGUCCCA 5943
1175 GACUCUGC C UGGCUCUG 461 CAGAGCCA CUGAUGAGGCCGUUAGGCCGAA ICAGAGUC 5944
1176 ACUCUGCC U GGCUCUGC 462 GCAGAGCC CUGAUGAGGCCGUUAGGCCGAA IGCAGAGU 5945
1180 UGCCUGGC U CUGCUGAG 463 CUCAGCAG CUGAUGAGGCCGUUAGGCCGAA ICCAGGCA 5946
1182 CCUGGCUC U GCUGAGCC 464 GGCUCAGC CUGAUGAGGCCGUUAGGCCGAA IAGCCAGG 5947
1185 GGCUCUGC U GAGCCCCC 465 GGGGGCUC CUGAUGAGGCCGUUAGGCCGAA ICAGAGCC 5948
1190 UGCUGAGC C CCCGCUCA 466 UGAGCGGG CUGAUGAGGCCGUUAGGCCGAA ICUCAGCA 5949
1191 GCUGAGCC C CCGCUCAC 467 GUGAGCGG CUGAUGAGGCCGUUAGGCCGAA IGCUCAGC 5950
1192 CUGAGCCC C CGCUCACU 468 AGUGAGCG CUGAUGAGGCCGUUAGGCCGAA IGGCUCAG 5951
1193 UGAGCCCC C GCUCACUG 469 CAGUGAGC CUGAUGAGGCCGUUAGGCCGAA IGGGCUCA 5952
1196 GCCCCCGC U CACUGCAG 470 CUGCAGUG CUGAUGAGGCCGUUAGGCCGAA ICGGGGGC 5953
1198 CCCCGCUC A CUGCAGUG 471 CACUGCAG CUGAUGAGGCCGUUAGGCCGAA IAGCGGGG 5954
1200 CCGCUCAC U GCAGUGCG 472 CGCACUGC CUGAUGAGGCCGUUAGGCCGAA IUGAGCGG 5955
1203 CUCACUGC A GUGCGGCC 473 GGCCGCAC CUGAUGAGGCCGUUAGGCCGAA ICAGUGAG 5956
1211 AGUGCGGC C CGAGGGCU 474 AGCCCUCG CUGAUGAGGCCGUUAGGCCGAA ICCGCACU 5957
1212 GUGCGGCC C GAGGGCUC 475 GAGCCCUC CUGAUGAGGCCGUUAGGCCGAA IGCCGCAC 5958
1219 CCGAGGGC U CCGAGCCA 476 UGGCUCGG CUGAUGAGGCCGUUAGGCCGAA ICCCUCGG 5959
1221 GAGGGCUC C GAGCCACC 477 GGUGGCUC CUGAUGAGGCCGUUAGGCCGAA IAGCCCUC 5960
1226 CUCCGAGC C ACCAGGGU 478 ACCCUGGU CUGAUGAGGCCGUUAGGCCGAA ICUCGGAG 5961
1227 UCCGAGCC A CCAGGGUU 479 AACCCUGG CUGAUGAGGCCGUUAGGCCGAA IGCUCGGA 5962
1229 CGAGCCAC C AGGGUUCC 480 GGAACCCU CUGAUGAGGCCGUUAGGCCGAA IUGGCUCG 5963
1230 GAGCCACC A GGGUUCCC 481 GGGAACCC CUGAUGAGGCCGUUAGGCCGAA IGUGGCUC 5964
1237 CAGGGUUC C CCACCUCG 482 CGAGGUGG CUGAUGAGGCCGUUAGGCCGAA IAACCCUG 5965
1238 AGGGUUCC C CACCUCGG 483 CCGAGGUG CUGAUGAGGCCGUUAGGCCGAA IGAACCCU 5966
1239 GGGUUCCC C ACCUCGGG 484 CCCGAGGU CUGAUGAGGCCGUUAGGCCGAA IGGAACCC 5967
1240 GGUUCCCC A CCUCGGGC 485 GCCCGAGG CUGAUGAGGCCGUUAGGCCGAA IGGGAACC 5968
1242 UUCCCCAC C UCGGGCCC 486 GGGCCCGA CUGAUGAGGCCGUUAGGCCGAA IUGGGGAA 5969
1243 UCCCCACC U CGGGCCCU 487 AGGGCCCG CUGAUGAGGCCGUUAGGCCGAA IGUGGGGA 5970
1249 CCUCGGGC C CUCGCCGG 488 CCGGCGAG CUGAUGAGGCCGUUAGGCCGAA ICCCGAGG 5971
1250 CUCGGGCC C UCGCCGGA 489 UCCGGCGA CUGAUGAGGCCGUUAGGCCGAA IGCCCGAG 5972
1251 UCGGGCCC U CGCCGGAG 490 CUCCGGCG CUGAUGAGGCCGUUAGGCCGAA IGGCCCGA 5973
1255 GCCCUCGC C GGAGGCCA 491 UGGCCUCC CUGAUGAGGCCGUUAGGCCGAA ICGAGGGC 5974
1262 CCGGAGGC C AGGCUGUU 492 AACAGCCU CUGAUGAGGCCGUUAGGCCGAA ICCUCCGG 5975
1263 CGGAGGCC A GGCUGUUC 493 GAACAGCC CUGAUGAGGCCGUUAGGCCGAA IGCCUCCG 5976
1267 GGCCAGGC U GUUCACGC 494 GCGUGAAC CUGAUGAGGCCGUUAGGCCGAA ICCUGGCC 5977
1272 GGCUGUUC A CGCAAGAA 495 UUCUUGCG CUGAUGAGGCCGUUAGGCCGAA IAACAGCC 5978
1276 GUUCACGC A AGAACCGC 496 GCGGUUCU CUGAUGAGGCCGUUAGGCCGAA ICGUGAAC 5979
1282 GCAAGAAC C GCACCCGC 497 GCGGGUGC CUGAUGAGGCCGUUAGGCCGAA IUUCUUGC 5980
1285 AGAACCGC A CCCGCAGC 498 GCUGCGGG CUGAUGAGGCCGUUAGGCCGAA ICGGUUCU 5981
1287 AACCGCAC C CGCAGCCA 499 UGGCUGCG CUGAUGAGGCCGUUAGGCCGAA IUGCGGUU 5982
1288 ACCGCACC C GCAGCCAC 500 GUGGCUGC CUGAUGAGGCCGUUAGGCCGAA IGUGCGGU 5983
1291 GCACCCGC A GCCACUGC 501 GCAGUGGC CUGAUGAGGCCGUUAGGCCGAA ICGGGUGC 5984 1294 CCCGCAGC C ACUGCCGU 502 ACGGCAGU CUGAUGAGGCCGUUAGGCCGAA ICUGCGGG 5985
1295 CCGCAGCC A CUGCCGUC 503 GACGGCAG CUGAUGAGGCCGUUAGGCCGAA IGCUGCGG 5986
1297 GCAGCCAC U GCCGUCUG 504 CAGACGGC CUGAUGAGGCCGUUAGGCCGAA IUGGCUGC 5987
1300 GCCACUGC C GUCUGGGC 505 GCCCAGAC CUGAUGAGGCCGUUAGGCCGAA ICAGUGGC 5988
1304 CUGCCGUC U GGGCCAGG 506 CCUGGCCC CUGAUGAGGCCGUUAGGCCGAA IACGGCAG 5989
1309 GUCUGGGC C AGGCAGGC 507 GCCUGCCU CUGAUGAGGCCGUUAGGCCGAA ICCCAGAC 5990
1310 UCUGGGCC A GGCAGGCA 508 UGCCUGCC CUGAUGAGGCCGUUAGGCCGAA IGCCCAGA 5991
1314 GGCCAGGC A GGCAGCGG 509 CCGCUGCC CUGAUGAGGCCGUUAGGCCGAA ICCUGGCC 5992
1318 AGGCAGGC A GCGGGGGU 510 ACCCCCGC CUGAUGAGGCCGUUAGGCCGAA ICCUGCCU 5993
1335 GGCGGGAC U GGUGACUC 511 GAGUCACC CUGAUGAGGCCGUUAGGCCGAA IUCCCGCC 5994
1342 CUGGUGAC U CAGAAGGC 512 GCCUUCUG CUGAUGAGGCCGUUAGGCCGAA IUCACCAG 5995
1344 GGUGACUC A GAAGGCUC 513 GAGCCUUC CUGAUGAGGCCGUUAGGCCGAA IAGUCACC 5996
1351 CAGAAGGC U CAGGUGCC 514 GGCACCUG CUGAUGAGGCCGUUAGGCCGAA ICCUUCUG 5997
1353 GAAGGCUC A GGUGCCCU 515 AGGGCACC CUGAUGAGGCCGUUAGGCCGAA IAGCCUUC 5998
1359 UCAGGUGC C CUACCCAG 516 CUGGGUAG CUGAUGAGGCCGUUAGGCCGAA ICACCUGA 5999
1360 CAGGUGCC C UACCCAGC 517 GCUGGGUA CUGAUGAGGCCGUUAGGCCGAA IGCACCUG 6000
1361 AGGUGCCC U ACCCAGCC 518 GGCUGGGU CUGAUGAGGCCGUUAGGCCGAA IGGCACCU 6001
1364 UGCCCUAC C CAGCCUCA 519 UGAGGCUG CUGAUGAGGCCGUUAGGCCGAA IUAGGGCA 6002
1365 GCCCUACC C AGCCUCAC 520 GUGAGGCU CUGAUGAGGCCGUUAGGCCGAA IGUAGGGC 6003
1366 CCCUACCC A GCCUCACC 521 GGUGAGGC CUGAUGAGGCCGUUAGGCCGAA IGGUAGGG 6004
1369 UACCCAGC C UCACCUGC 522 GCAGGUGA CUGAUGAGGCCGUUAGGCCGAA ICUGGGUA 6005
1370 ACCCAGCC U CACCUGCA 523 UGCAGGUG CUGAUGAGGCCGUUAGGCCGAA IGCUGGGU 6006
1372 CCAGCCUC A CCUGCAGC 524 GCUGCAGG CUGAUGAGGCCGUUAGGCCGAA IAGGCUGG 6007
1374 AGCCUCAC C UGCAGCCU 525 AGGCUGCA CUGAUGAGGCCGUUAGGCCGAA IUGAGGCU 6008
1375 GCCUCACC U GCAGCCUC 526 GAGGCUGC CUGAUGAGGCCGUUAGGCCGAA IGUGAGGC 6009
1378 UCACCUGC A GCCUCACC 527 GGUGAGGC CUGAUGAGGCCGUUAGGCCGAA ICAGGUGA 6010
1381 CCUGCAGC C UCACCCCC 528 GGGGGUGA CUGAUGAGGCCGUUAGGCCGAA ICUGCAGG 6011
1382 CUGCAGCC U CACCCCCC 529 GGGGGGUG CUGAUGAGGCCGUUAGGCCGAA IGCUGCAG 6012
1384 GCAGCCUC A CCCCCCUG 530 CAGGGGGG CUGAUGAGGCCGUUAGGCCGAA IAGGCUGC 6013
1386 AGCCUCAC C CCCCUGGG 531 CCCAGGGG CUGAUGAGGCCGUUAGGCCGAA IUGAGGCU 6014
1387 GCCUCACC C CCCUGGGC 532 GCCCAGGG CUGAUGAGGCCGUUAGGCCGAA IGUGAGGC 6015
1388 CCUCACCC C CCUGGGCC 533 GGCCCAGG CUGAUGAGGCCGUUAGGCCGAA IGGUGAGG 6016
1389 CUCACCCC C CUGGGCCU 534 AGGCCCAG CUGAUGAGGCCGUUAGGCCGAA IGGGUGAG 6017
1390 UCACCCCC C UGGGCCUG 535 CAGGCCCA CUGAUGAGGCCGUUAGGCCGAA IGGGGUGA 6018
1391 CACCCCCC U GGGCCUGG 536 CCAGGCCC CUGAUGAGGCCGUUAGGCCGAA IGGGGGUG 6019
1396 CCCUGGGC C UGGCGCUG 537 CAGCGCCA CUGAUGAGGCCGUUAGGCCGAA ICCCAGGG 6020
1397 CCUGGGCC U GGCGCUGG 538 CCAGCGCC CUGAUGAGGCCGUUAGGCCGAA IGCCCAGG 6021
1403 CCUGGCGC U GGUGCUGU 539 ACAGCACC CUGAUGAGGCCGUUAGGCCGAA ICGCCAGG 6022
1409 GCUGGUGC U GUGGACAG 540 CUGUCCAC CUGAUGAGGCCGUUAGGCCGAA ICACCAGC 6023
1416 CUGUGGAC A GUGCUUGG 541 CCAAGCAC CUGAUGAGGCCGUUAGGCCGAA IUCCACAG 6024
1421 GACAGUGC U UGGGCCCU 542 AGGGCCCA CUGAUGAGGCCGUUAGGCCGAA ICACUGUC 6025
1427 GCUUGGGC C CUGCUGAC 543 GUCAGCAG CUGAUGAGGCCGUUAGGCCGAA ICCCAAGC 6026
1428 CUUGGGCC C UGCUGACC 544 GGUCAGCA CUGAUGAGGCCGUUAGGCCGAA IGCCCAAG 6027
1429 UUGGGCCC U GCUGACCC 545 GGGUCAGC CUGAUGAGGCCGUUAGGCCGAA IGGCCCAA 6028
1432 GGCCCUGC U GACCCCCA 546 UGGGGGUC CUGAUGAGGCCGUUAGGCCGAA ICAGGGCC 6029
Input Sequence = AB020693. Cut Site = CH/.
Arm Length = 8. Core Sequence = CUGAUGAG GCCGUUAGGC CGAA
AB020693 (Homo sapiens mRNA for KIAA0886 protein (Nogo-A); 4053 bp)
Underlined region can be any X sequence or linker, as described herein. I = Inosine Table V: Human NOGO Receptor Zinzyme and Substrate Sequence
Pos Substrate Seq Zinzyme Rz Seq ID ID
22 UGAAGAGG G CGUCCGCU 547 AGCGGACG GCCGAAAGGCGAGUGAGGUCU CCUCUUCA 6030
24 AAGAGGGC G UCCGCUGG 548 CCAGCGGA GCCGAAAGGCGAGUGAGGUCU GCCCUCUU 6031
28 GGGCGUCC G CUGGAGGG 549 CCCUCCAG GCCGAAAGGCGAGUGAGGUCU GGACGCCC 6032
38 UGGAGGGA G CCGGCUGC 550 GCAGCCGG GCCGAAAGGCGAGUGAGGUCU UCCCUCCA 6033
42 GGGAGCCG G CUGCUGGC 551 GCCAGCAG GCCGAAAGGCGAGUGAGGUCU CGGCUCCC 6034
45 AGCCGGCU G CUGGCAUG 552 CAUGCCAG GCCGAAAGGCGAGUGAGGUCU AGCCGGCU 6035
49 GGCUGCUG G CAUGGGUG 553 CACCCAUG GCCGAAAGGCGAGUGAGGUCU CAGCAGCC 6036
55 UGGCAUGG G UGCUGUGG 554 CCACAGCA GCCGAAAGGCGAGUGAGGUCU CCAUGCCA 6037
57 GCAUGGGU G CUGUGGCU 555 AGCCACAG GCCGAAAGGCGAGUGAGGUCU ACCCAUGC 6038
60 UGGGUGCU G UGGCUGCA 556 UGCAGCCA GCCGAAAGGCGAGUGAGGUCU AGCACCCA 6039
63 GUGCUGUG G CUGCAGGC 557 GCCUGCAG GCCGAAAGGCGAGUGAGGUCU CACAGCAC 6040
66 CUGUGGCU G CAGGCCUG 558 CAGGCCUG GCCGAAAGGCGAGUGAGGUCU AGCCACAG 6041
70 GGCUGCAG G CCUGGCAG 559 CUGCCAGG GCCGAAAGGCGAGUGAGGUCU CUGCAGCC 6042
75 CAGGCCUG G CAGGUGGC 560 GCCACCUG GCCGAAAGGCGAGUGAGGUCU CAGGCCUG 6043
79 CCUGGCAG G UGGCAGCC 561 GGCUGCCA GCCGAAAGGCGAGUGAGGUCU CUGCCAGG 6044
82 GGCAGGUG G CAGCCCCA 562 UGGGGCUG GCCGAAAGGCGAGUGAGGUCU CACCUGCC 6045
85 AGGUGGCA G CCCCAUGC 563 GCAUGGGG GCCGAAAGGCGAGUGAGGUCU UGCCACCU 6046
92 AGCCCCAU G CCCAGGUG 56 CACCUGGG GCCGAAAGGCGAGUGAGGUCU AUGGGGCU 6047
98 AUGCCCAG G UGCCUGCG 565 CGCAGGCA GCCGAAAGGCGAGUGAGGUCU CUGGGCAU 6048
100 GCCCAGGU G CCUGCGUA 566 UACGCAGG GCCGAAAGGCGAGUGAGGUCU ACCUGGGC 6049
104 AGGUGCCU G CGUAUGCU 567 AGCAUACG GCCGAAAGGCGAGUGAGGUCU AGGCACCU 6050
106 GUGCCUGC G UAUGCUAC 568 GUAGCAUA GCCGAAAGGCGAGUGAGGUCU GCAGGCAC 6051
110 CUGCGUAU G CUACAAUG 569 CAUUGUAG GCCGAAAGGCGAGUGAGGUCU AUACGCAG 6052
120 UACAAUGA G CCCAAGGU 570 ACCUUGGG GCCGAAAGGCGAGUGAGGUCU UCAUUGUA 6053
127 AGCCCAAG G UGACGACA 571 UGUCGUCA GCCGAAAGGCGAGUGAGGUCU CUUGGGCU 6054
137 GACGACAA G CUGCCCCC 572 GGGGGCAG GCCGAAAGGCGAGUGAGGUCU UUGUCGUC 6055
140 GACAAGCU G CCCCCAGC 573 GCUGGGGG GCCGAAAGGCGAGUGAGGUCU AGCUUGUC 6056
147 UGCCCCCA G CAGGGCCU 574 AGGCCCUG GCCGAAAGGCGAGUGAGGUCU UGGGGGCA 6057
152 CCAGCAGG G CCUGCAGG 575 CCUGCAGG GCCGAAAGGCGAGUGAGGUCU CCUGCUGG 6058
156 CAGGGCCU G CAGGCUGU 576 ACAGCCUG GCCGAAAGGCGAGUGAGGUCU AGGCCCUG 6059
160 GCCUGCAG G CUGUGCCC 577 GGGCACAG GCCGAAAGGCGAGUGAGGUCU CUGCAGGC 6060
163 UGCAGGCU G UGCCCGUG 578 CACGGGCA GCCGAAAGGCGAGUGAGGUCU AGCCUGCA 6061
165 CAGGCUGU G CCCGUGGG 579 CCCACGGG GCCGAAAGGCGAGUGAGGUCU ACAGCCUG 6062
169 CUGUGCCC G UGGGCAUC 580 GAUGCCCA GCCGAAAGGCGAGUGAGGUCU GGGCACAG 6063
173 GCCCGUGG G CAUCCCUG 581 CAGGGAUG GCCGAAAGGCGAGUGAGGUCU CCACGGGC 6064
181 GCAUCCCU G CUGCCAGC 582 GCUGGCAG GCCGAAAGGCGAGUGAGGUCU AGGGAUGC 6065
184 UCCCUGCU G CCAGCCAG 583 CUGGCUGG GCCGAAAGGCGAGUGAGGUCU AGCAGGGA 6066
188 UGCUGCCA G CCAGCGCA 584 UGCGCUGG GCCGAAAGGCGAGUGAGGUCU UGGCAGCA 6067
192 GCCAGCCA G CGCAUCUU 585 AAGAUGCG GCCGAAAGGCGAGUGAGGUCU UGGCUGGC 6068
194 CAGCCAGC G CAUCUUCC 586 GGAAGAUG GCCGAAAGGCGAGUGAGGUCU GCUGGCUG 6069
204 AUCUUCCU G CACGGCAA 587 UUGCCGUG GCCGAAAGGCGAGUGAGGUCU AGGAAGAU 6070
209 CCUGCACG G CAACCGCA 588 UGCGGUUG GCCGAAAGGCGAGUGAGGUCU CGUGCAGG 6071
572 CCUGCACG G CAACCGCA 588 UGCGGUUG GCCGAAAGGCGAGUGAGGUCU CGUGCAGG 6071
215 CGGCAACC G CAUCUCGC 589 GCGAGAUG GCCGAAAGGCGAGUGAGGUCU GGUUGCCG 6072
222 CGCAUCUC G CAUGUGCC 590 GGCACAUG GCCGAAAGGCGAGUGAGGUCU GAGAUGCG 6073
226 UCUCGCAU G UGCCAGCU 591 AGCUGGCA GCCGAAAGGCGAGUGAGGUCU AUGCGAGA 6074
228 UCGCAUGU G CCAGCUGC 592 GCAGCUGG GCCGAAAGGCGAGUGAGGUCU ACAUGCGA 6075 232 AUGUGCCA G CUGCCAGC 593 GCUGGCAG GCCGAAAGGCGAGUGAGGUCU UGGCACAU 6076
235 UGCCAGCU G CCAGCUUC 594 GAAGCUGG GCCGAAAGGCGAGUGAGGUCU AGCUGGCA 6077
239 AGCUGCCA G CUUCCGUG 595 CACGGAAG GCCGAAAGGCGAGUGAGGUCU UGGCAGCU 6078
245 CAGCUUCC G UGCCUGCC 596 GGCAGGCA GCCGAAAGGCGAGUGAGGUCU GGAAGCUG 6079
247 GCUUCCGU G CCUGCCGC 597 GCGGCAGG GCCGAAAGGCGAGUGAGGUCU ACGGAAGC 6080
251 CCGUGCCU G CCGCAACC 598 GGUUGCGG GCCGAAAGGCGAGUGAGGUCU AGGCACGG 6081
254 UGCCUGCC G CAACCUCA 599 UGAGGUUG GCCGAAAGGCGAGUGAGGUCU GGCAGGCA 6082
270 ACCAUCCU G UGGCUGCA 600 UGCAGCCA GCCGAAAGGCGAGUGAGGUCU AGGAUGGU 6083
273 AUCCUGUG G CUGCACUC 601 GAGUGCAG GCCGAAAGGCGAGUGAGGUCU CACAGGAU 6084
276 CUGUGGCU G CACUCGAA 602 UUCGAGUG GCCGAAAGGCGAGUGAGGUCU AGCCACAG 6085
286 ACUCGAAU G UGCUGGCC 603 GGCCAGCA GCCGAAAGGCGAGUGAGGUCU AUUCGAGU 6086
288 UCGAAUGU G CUGGCCCG 604 CGGGCCAG GCCGAAAGGCGAGUGAGGUCU ACAUUCGA 6087
292 AUGUGCUG G CCCGAAUU 605 AAUUCGGG GCCGAAAGGCGAGUGAGGUCU CAGCACAU 6088
304 GAAUUGAU G CGGCUGCC 606 GGCAGCCG GCCGAAAGGCGAGUGAGGUCU AUCAAUUC 6089
307 UUGAUGCG G CUGCCUUC 607 GAAGGCAG GCCGAAAGGCGAGUGAGGUCU CGCAUCAA 6090
310 AUGCGGCU G CCUUCACU 608 AGUGAAGG GCCGAAAGGCGAGUGAGGUCU AGCCGCAU 6091
320 CUUCACUG G CCUGGCCC 609 GGGCCAGG GCCGAAAGGCGAGUGAGGUCU CAGUGAAG 6092
325 CUGGCCUG G CCCUCCUG 610 CAGGAGGG GCCGAAAGGCGAGUGAGGUCU CAGGCCAG 6093
336 CUCCUGGA G CAGCUGGA 611 UCCAGCUG GCCGAAAGGCGAGUGAGGUCU UCCAGGAG 6094
339 CUGGAGCA G CUGGACCU 612 AGGUCCAG GCCGAAAGGCGAGUGAGGUCU UGCUCCAG 6095
350 GGACCUCA G CGAUAAUG 613 CAUUAUCG GCCGAAAGGCGAGUGAGGUCU UGAGGUCC 6096
358 GCGAUAAU G CACAGCUC 614 GAGCUGUG GCCGAAAGGCGAGUGAGGUCU AUUAUCGC 6097
363 AAUGCACA G CUCCGGUC 615 GACCGGAG GCCGAAAGGCGAGUGAGGUCU UGUGCAUU 6098
369 CAGCUCCG G UCUGUGGA 616 UCCACAGA GCCGAAAGGCGAGUGAGGUCU CGGAGCUG 6099
373 UCCGGUCU G UGGACCCU 617 AGGGUCCA GCCGAAAGGCGAGUGAGGUCU AGACCGGA 6100
382 UGGACCCU G CCACAUUC 618 GAAUGUGG GCCGAAAGGCGAGUGAGGUCU AGGGUCCA 6101
395 AUUCCACG G CCUGGGCC 619 GGCCCAGG GCCGAAAGGCGAGUGAGGUCU CGUGGAAU 6102
401 CGGCCUGG G CCGCCUAC 620 GUAGGCGG GCCGAAAGGCGAGUGAGGUCU CCAGGCCG 6103
404 CCUGGGCC G CCUACACA 621 UGUGUAGG GCCGAAAGGCGAGUGAGGUCU GGCCCAGG 6104
414 CUACACAC G CUGCACCU 622 AGGUGCAG GCCGAAAGGCGAGUGAGGUCU GUGUGUAG 6105
417 CACACGCU G CACCUGGA 623 UCCAGGUG GCCGAAAGGCGAGUGAGGUCU AGCGUGUG 6106
428 CCUGGACC G CUGCGGCC 624 GGCCGCAG GCCGAAAGGCGAGUGAGGUCU GGUCCAGG 6107
431 GGACCGCU G CGGCCUGC 625 GCAGGCCG GCCGAAAGGCGAGUGAGGUCU AGCGGUCC 6108
434 CCGCUGCG G CCUGCAGG 626 CCUGCAGG GCCGAAAGGCGAGUGAGGUCU CGCAGCGG 6109
438 UGCGGCCU G CAGGAGCU 627 AGCUCCUG GCCGAAAGGCGAGUGAGGUCU AGGCCGCA 6110
444 CUGCAGGA G CUGGGCCC 628 GGGCCCAG GCCGAAAGGCGAGUGAGGUCU UCCUGCAG 6111
449 GGAGCUGG G CCCGGGGC 629 GCCCCGGG GCCGAAAGGCGAGUGAGGUCU CCAGCUCC 6112
456 GGCCCGGG G CUGUUCCG 630 CGGAACAG GCCGAAAGGCGAGUGAGGUCU CCCGGGCC 6113
459 CCGGGGCU G UUCCGCGG 631 CCGCGGAA GCCGAAAGGCGAGUGAGGUCU AGCCCCGG 6114
464 GCUGUUCC G CGGCCUGG 632 CCAGGCCG GCCGAAAGGCGAGUGAGGUCU GGAACAGC 6115
467 GUUCCGCG G CCUGGCUG 633 CAGCCAGG GCCGAAAGGCGAGUGAGGUCU CGCGGAAC 6116 72 GCGGCCUG G CUGCCCUG 634 CAGGGCAG GCCGAAAGGCGAGUGAGGUCU CAGGCCGC 6117
475 GCCUGGCU G CCCUGCAG 635 CUGCAGGG GCCGAAAGGCGAGUGAGGUCU AGCCAGGC 6118
480 GCUGCCCU G CAGUACCU 636 AGGUACUG GCCGAAAGGCGAGUGAGGUCU AGGGCAGC 6119
483 GCCCUGCA G UACCUCUA 637 UAGAGGUA GCCGAAAGGCGAGUGAGGUCU UGCAGGGC 6120
495 CUCUACCU G CAGGACAA 638 UUGUCCUG GCCGAAAGGCGAGUGAGGUCU AGGUAGAG 6121
505 AGGACAAC G CGCUGCAG 639 CUGCAGCG GCCGAAAGGCGAGUGAGGUCU GUUGUCCU 6122
507 GACAACGC G CUGCAGGC 640 GCCUGCAG GCCGAAAGGCGAGUGAGGUCU GCGUUGUC 6123
510 AACGCGCU G CAGGCACU 641 AGUGCCUG GCCGAAAGGCGAGUGAGGUCU AGCGCGUU 6124
514 CGCUGCAG G CACUGCCU 642 AGGCAGUG GCCGAAAGGCGAGUGAGGUCU CUGCAGCG 6125
519 CAGGCACU G CCUGAUGA 643 UCAUCAGG GCCGAAAGGCGAGUGAGGUCU AGUGCCUG 6126 536 CACCUUCC G CGACCUGG 644 CCAGGUCG GCCGAAAGGCGAGUGAGGUCU GGAAGGUG 6127
545 CGACCUGG G CAACCUCA 645 UGAGGUUG GCCGAAAGGCGAGUGAGGUCU CCAGGUCG 6128
567 CUCUUCCU G CACGGCAA 646 UUGCCGUG GCCGAAAGGCGAGUGAGGUCU AGGAAGAG 6129
578 CGGCAACC G CAUCUCCA 647 UGGAGAUG GCCGAAAGGCGAGUGAGGUCU GGUUGCCG 6130
587 CAUCUCCA G CGUGCCCG 648 CGGGCACG GCCGAAAGGCGAGUGAGGUCU UGGAGAUG 6131
589 UCUCCAGC G UGCCCGAG 649 CUCGGGCA GCCGAAAGGCGAGUGAGGUCU GCUGGAGA 6132
591 UCCAGCGU G CCCGAGCG 650 CGCUCGGG GCCGAAAGGCGAGUGAGGUCU ACGCUGGA 6133
597 GUGCCCGA G CGCGCCUU 651 AAGGCGCG GCCGAAAGGCGAGUGAGGUCU UCGGGCAC 6134
599 GCCCGAGC G CGCCUUCC 652 GGAAGGCG GCCGAAAGGCGAGUGAGGUCU GCUCGGGC 6135
601 CCGAGCGC G CCUUCCGU 653 ACGGAAGG GCCGAAAGGCGAGUGAGGUCU GCGCUCGG 6136
608 CGCCUUCC G UGGGCUGC 654 GCAGCCCA GCCGAAAGGCGAGUGAGGUCU GGAAGGCG 6137
612 UUCCGUGG G CUGCACAG 655 CUGUGCAG GCCGAAAGGCGAGUGAGGUCU CCACGGAA 6138
615 CGUGGGCU G CACAGCCU 656 AGGCUGUG GCCGAAAGGCGAGUGAGGUCU AGCCCACG 6139
620 GCUGCACA G CCUCGACC 657 GGUCGAGG GCCGAAAGGCGAGUGAGGUCU UGUGCAGC 6140
629 CCUCGACC G UCUCCUAC 658 GUAGGAGA GCCGAAAGGCGAGUGAGGUCU GGUCGAGG 6141
639 CUCCUACU G CACCAGAA 659 UUCUGGUG GCCGAAAGGCGAGUGAGGUCU AGUAGGAG 6142
650 CCAGAACC G CGUGGCCC 660 GGGCCACG GCCGAAAGGCGAGUGAGGUCU GGUUCUGG 6143
652 AGAACCGC G UGGCCCAU 661 AUGGGCCA GCCGAAAGGCGAGUGAGGUCU GCGGUUCU 6144
655 ACCGCGUG G CCCAUGUG 662 CACAUGGG GCCGAAAGGCGAGUGAGGUCU CACGCGGU 6145
661 UGGCCCAU G UGCACCCG 663 CGGGUGCA GCCGAAAGGCGAGUGAGGUCU AUGGGCCA 6146
663 GCCCAUGU G CACCCGCA 664 UGCGGGUG GCCGAAAGGCGAGUGAGGUCU ACAUGGGC 6147
669 GUGCACCC G CAUGCCUU 665 AAGGCAUG GCCGAAAGGCGAGUGAGGUCU GGGUGCAC 6148
673 ACCCGCAU G CCUUCCGU 666 ACGGAAGG GCCGAAAGGCGAGUGAGGUCU AUGCGGGU 6149
680 UGCCUUCC G UGACCUUG 667 CAAGGUCA GCCGAAAGGCGAGUGAGGUCU GGAAGGCA 6150
689 UGACCUUG G CCGCCUCA 668 UGAGGCGG GCCGAAAGGCGAGUGAGGUCU CAAGGUCA 6151
692 CCUUGGCC G CCUCAUGA 669 UCAUGAGG GCCGAAAGGCGAGUGAGGUCU GGCCAAGG 6152
711 CUCUAUCU G UUUGCCAA 670 UUGGCAAA GCCGAAAGGCGAGUGAGGUCU AGAUAGAG 6153
715 AUCUGUUU G CCAACAAU 671 AUUGUUGG GCCGAAAGGCGAGUGAGGUCU AAACAGAU 6154
730 AUCUAUCA G CGCUGCCC 672 GGGCAGCG GCCGAAAGGCGAGUGAGGUCU UGAUAGAU 6155
732 CUAUCAGC G CUGCCCAC 673 GUGGGCAG GCCGAAAGGCGAGUGAGGUCU GCUGAUAG 6156
735 UCAGCGCU G CCCACUGA 674 UCAGUGGG GCCGAAAGGCGAGUGAGGUCU AGCGCUGA 6157
745 CCACUGAG G CCCUGGCC 675 GGCCAGGG GCCGAAAGGCGAGUGAGGUCU CUCAGUGG 6158
751 AGGCCCUG G CCCCCCUG 676 CAGGGGGG GCCGAAAGGCGAGUGAGGUCU CAGGGCCU 6159
759 GCCCCCCU G CGUGCCCU 677 AGGGCACG GCCGAAAGGCGAGUGAGGUCU AGGGGGGC 6160
761 CCCCCUGC G UGCCCUGC 678 GCAGGGCA GCCGAAAGGCGAGUGAGGUCU GCAGGGGG 6161
763 CCCUGCGU G CCCUGCAG 679 CUGCAGGG GCCGAAAGGCGAGUGAGGUCU ACGCAGGG 6162
768 CGUGCCCU G CAGUACCU 680 AGGUACUG GCCGAAAGGCGAGUGAGGUCU AGGGCACG 6163
771 GCCCUGCA G UACCUGAG 681 CUCAGGUA GCCGAAAGGCGAGUGAGGUCU UGCAGGGC 6164
780 UACCUGAG G CUCAACGA 682 UCGUUGAG GCCGAAAGGCGAGUGAGGUCU CUCAGGUA 6165
799 ACCCCUGG G UGUGUGAC 683 GUCACACA GCCGAAAGGCGAGUGAGGUCU CCAGGGGU 6166
801 CCCUGGGU G UGUGACUG 684 CAGUCACA GCCGAAAGGCGAGUGAGGUCU ACCCAGGG 6167
803 CUGGGUGU G UGACUGCC 685 GGCAGUCA GCCGAAAGGCGAGUGAGGUCU ACACCCAG 6168
809 GUGUGACU G CCGGGCAC 686 GUGCCCGG GCCGAAAGGCGAGUGAGGUCU AGUCACAC 6169
814 ACUGCCGG G CACGCCCA 687 UGGGCGUG GCCGAAAGGCGAGUGAGGUCU CCGGCAGU 6170
818 CCGGGCAC G CCCACUCU 688 AGAGUGGG GCCGAAAGGCGAGUGAGGUCU GUGCCCGG 6171
829 CACUCUGG G CCUGGCUG 689 CAGCCAGG GCCGAAAGGCGAGUGAGGUCU CCAGAGUG 6172
834 UGGGCCUG G CUGCAGAA 690 UUCUGCAG GCCGAAAGGCGAGUGAGGUCU CAGGCCCA 6173
837 GCCUGGCU G CAGAAGUU 691 AACUUCUG GCCGAAAGGCGAGUGAGGUCU AGCCAGGC 6174
843 CUGCAGAA G UUCCGCGG 692 CCGCGGAA GCCGAAAGGCGAGUGAGGUCU UUCUGCAG 6175
848 GAAGUUCC G CGGCUCCU 693 AGGAGCCG GCCGAAAGGCGAGUGAGGUCU GGAACUUC 6176
851 GUUCCGCG G CUCCUCCU 694 AGGAGGAG GCCGAAAGGCGAGUGAGGUCU CGCGGAAC 6177 865 CCUCCGAG G UGCCCUGC 695 GCAGGGCA GCCGAAAGGCGAGUGAGGUCU CUCGGAGG 6178
867 UCCGAGGU G CCCUGCAG 696 CUGCAGGG GCCGAAAGGCGAGUGAGGUCU ACCUCGGA 6179
872 GGUGCCCU G CAGCCUCC 697 GGAGGCUG GCCGAAAGGCGAGUGAGGUCU AGGGCACC 6180
875 GCCCUGCA G CCUCCCGC 698 GCGGGAGG GCCGAAAGGCGAGUGAGGUCU UGCAGGGC 6181
882 AGCCUCCC G CAACGCCU 699 AGGCGUUG GCCGAAAGGCGAGUGAGGUCU GGGAGGCU 6182
887 CCCGCAAC G CCUGGCUG 700 CAGCCAGG GCCGAAAGGCGAGUGAGGUCU GUUGCGGG 6183
892 AACGCCUG G CUGGCCGU 701 ACGGCCAG GCCGAAAGGCGAGUGAGGUCU CAGGCGUU 6184
896 CCUGGCUG G CCGUGACC 702 GGUCACGG GCCGAAAGGCGAGUGAGGUCU CAGCCAGG 6185
899 GGCUGGCC G UGACCUCA 703 UGAGGUCA GCCGAAAGGCGAGUGAGGUCU GGCCAGCC 6186
911 CCUCAAAC G CCUAGCUG 704 CAGCUAGG GCCGAAAGGCGAGUGAGGUCU GUUUGAGG 6187
916 AACGCCUA G CUGCCAAU 705 AUUGGCAG GCCGAAAGGCGAGUGAGGUCU UAGGCGUU 6188
919 GCCUAGCU G CCAAUGAC 706 GUCAUUGG GCCGAAAGGCGAGUGAGGUCU AGCUAGGC 6189
930 AAUGACCU G CAGGGCUG 707 CAGCCCUG GCCGAAAGGCGAGUGAGGUCU AGGUCAUU 6190
935 CCUGCAGG G CUGCGCUG 708 CAGCGCAG GCCGAAAGGCGAGUGAGGUCU CCUGCAGG 6191
938 GCAGGGCU G CGCUGUGG 709 CCACAGCG GCCGAAAGGCGAGUGAGGUCU AGCCCUGC 6192
940 AGGGCUGC G CUGUGGCC 710 GGCCACAG GCCGAAAGGCGAGUGAGGUCU GCAGCCCU 6193
943 GCUGCGCU G UGGCCACC 711 GGUGGCCA GCCGAAAGGCGAGUGAGGUCU AGCGCAGC 6194
946 GCGCUGUG G CCACCGGC 712 GCCGGUGG GCCGAAAGGCGAGUGAGGUCU CACAGCGC 6195
953 GGCCACCG G CCCUUACC 713 GGUAAGGG GCCGAAAGGCGAGUGAGGUCU CGGUGGCC 6196
977 CUGGACCG G CAGGGCCA 714 UGGCCCUG GCCGAAAGGCGAGUGAGGUCU CGGUCCAG 6197
982 CCGGCAGG G CCACCGAU 715 AUCGGUGG GCCGAAAGGCGAGUGAGGUCU CCUGCCGG 6198
996 GAUGAGGA G CCGCUGGG 716 CCCAGCGG GCCGAAAGGCGAGUGAGGUCU UCCUCAUC 6199
999 GAGGAGCC G CUGGGGCU 717 AGCCCCAG GCCGAAAGGCGAGUGAGGUCU GGCUCCUC 6200
1005 CCGCUGGG G CUUCCCAA 718 UUGGGAAG GCCGAAAGGCGAGUGAGGUCU CCCAGCGG 6201
1014 CUUCCCAA G UGCUGCCA 719 UGGCAGCA GCCGAAAGGCGAGUGAGGUCU UUGGGAAG 6202
1016 UCCCAAGU G CUGCCAGC 720 GCUGGCAG GCCGAAAGGCGAGUGAGGUCU ACUUGGGA 6203
1019 CAAGUGCU G CCAGCCAG 721 CUGGCUGG GCCGAAAGGCGAGUGAGGUCU AGCACUUG 6204
1023 UGCUGCCA G CCAGAUGC 722 GCAUCUGG GCCGAAAGGCGAGUGAGGUCU UGGCAGCA 6205
1030 AGCCAGAU G CCGCUGAC 723 GUGAGCGG GCCGAAAGGCGAGUGAGGUCU AUCUGGCU 6206
1033 CAGAUGCC G CUGACAAG 724 CUUGUCAG GCCGAAAGGCGAGUGAGGUCU GGCAUCUG 6207
1042 CUGACAAG G CCUCAGUA 725 UACUGAGG GCCGAAAGGCGAGUGAGGUCU CUUGUCAG 6208
1048 AGGCCUCA G UACUGGAG 726 CUCCAGUA GCCGAAAGGCGAGUGAGGUCU UGAGGCCU 6209
1056 GUACUGGA G CCUGGAAG 727 CUUCCAGG GCCGAAAGGCGAGUGAGGUCU UCCAGUAC 6210
1069 GAAGACCA G CUUCGGCA 728 UGCCGAAG GCCGAAAGGCGAGUGAGGUCU UGGUCUUC 6211
1075 CAGCUUCG G CAGGCAAU 729 AUUGCCUG GCCGAAAGGCGAGUGAGGUCU CGAAGCUG 6212
1079 UUCGGCAG G CAAUGCGC 730 GCGCAUUG GCCGAAAGGCGAGUGAGGUCU CUGCCGAA 6213
1084 CAGGCAAU G CGCUGAAG 731 CUUCAGCG GCCGAAAGGCGAGUGAGGUCU AUUGCCUG 6214
1086 GGCAAUGC G CUGAAGGG 732 CCCUUCAG GCCGAAAGGCGAGUGAGGUCU GCAUUGCC 6215
1097 GAAGGGAC G CGUGCCGC 733 GCGGCACG GCCGAAAGGCGAGUGAGGUCU GUCCCUUC 6216
1099 AGGGACGC G UGCCGCCC 734 GGGCGGCA GCCGAAAGGCGAGUGAGGUCU GCGUCCCU 6217
1101 GGACGCGU G CCGCCCGG 735 CCGGGCGG GCCGAAAGGCGAGUGAGGUCU ACGCGUCC 6218
1104 CGCGUGCC G CCCGGUGA 736 UCACCGGG GCCGAAAGGCGAGUGAGGUCU GGCACGCG 6219
1109 GCCGCCCG G UGACAGCC 737 GGCUGUCA GCCGAAAGGCGAGUGAGGUCU CGGGCGGC 6220
1115 CGGUGACA G CCCGCCGG 738 CCGGCGGG GCCGAAAGGCGAGUGAGGUCU UGUCACCG 6221
1119 GACAGCCC G CCGGGCAA 739 UUGCCCGG GCCGAAAGGCGAGUGAGGUCU GGGCUGUC 6222
1124 CCCGCCGG G CAACGGCU 740 AGCCGUUG GCCGAAAGGCGAGUGAGGUCU CCGGCGGG 6223
1130 GGGCAACG G CUCUGGCC 741 GGCCAGAG GCCGAAAGGCGAGUGAGGUCU CGUUGCCC 6224
1136 CGGCUCUG G CCCACGGC 742 GCCGUGGG GCCGAAAGGCGAGUGAGGUCU CAGAGCCG 6225
1143 GGCCCACG G CACAUCAA 743 UUGAUGUG GCCGAAAGGCGAGUGAGGUCU CGUGGGCC 6226
1173 GGGACUCU G CCUGGCUC 744 GAGCCAGG GCCGAAAGGCGAGUGAGGUCU AGAGUCCC 6227
1178 UCUGCCUG G CUCUGCUG 745 CAGCAGAG GCCGAAAGGCGAGUGAGGUCU CAGGCAGA 6228 1183 CUGGCUCU G CUGAGCCC 746 GGGCUCAG GCCGAAAGGCGAGUGAGGUCU AGAGCCAG 6229
1188 UCUGCUGA G CCCCCGCU 747 AGCGGGGG GCCGAAAGGCGAGUGAGGUCU UCAGCAGA 6230
1194 GAGCCCCC G CUCACUGC 748 GCAGUGAG GCCGAAAGGCGAGUGAGGUCU GGGGGCUC 6231
1201 CGCUCACU G CAGUGCGG 749 CCGCACUG GCCGAAAGGCGAGUGAGGUCU AGUGAGCG 6232
1204 UCACUGCA G UGCGGCCC 750 GGGCCGCA GCCGAAAGGCGAGUGAGGUCU UGCAGUGA 6233
1206 ACUGCAGU G CGGCCCGA 751 UCGGGCCG GCCGAAAGGCGAGUGAGGUCU ACUGCAGU 6234
1209 GCAGUGCG G CCCGAGGG 752 CCCUCGGG GCCGAAAGGCGAGUGAGGUCU CGCACUGC 6235
1217 GCCCGAGG G CUCCGAGC 753 GCUCGGAG GCCGAAAGGCGAGUGAGGUCU CCUCGGGC 6236
1224 GGCUCCGA G CCACCAGG 754 CCUGGUGG GCCGAAAGGCGAGUGAGGUCU UCGGAGCC 6237
1233 CCACCAGG G UUCCCCAC 755 GUGGGGAA GCCGAAAGGCGAGUGAGGUCU CCUGGUGG 6238
1247 CACCUCGG G CCCUCGCC 756 GGCGAGGG GCCGAAAGGCGAGUGAGGUCU CCGAGGUG 6239
1253 GGGCCCUC G CCGGAGGC 757 GCCUCCGG GCCGAAAGGCGAGUGAGGUCU GAGGGCCC 6240
1260 CGCCGGAG G CCAGGCUG 758 CAGCCUGG GCCGAAAGGCGAGUGAGGUCU CUCCGGCG 6241
1265 GAGGCCAG G CUGUUCAC 759 GUGAACAG GCCGAAAGGCGAGUGAGGUCU CUGGCCUC 6242
1268 GCCAGGCU G UUCACGCA 760 UGCGUGAA GCCGAAAGGCGAGUGAGGUCU AGCCUGGC 6243
1274 CUGUUCAC G CAAGAACC 761 GGUUCUUG GCCGAAAGGCGAGUGAGGUCU GUGAACAG 6244
1283 CAAGAACC G CACCCGCA 762 UGCGGGUG GCCGAAAGGCGAGUGAGGUCU GGUUCUUG 6245
1289 CCGCACCC G CAGCCACU 763 AGUGGCUG GCCGAAAGGCGAGUGAGGUCU GGGUGCGG 6246
1292 CACCCGCA G CCACUGCC 764 GGCAGUGG GCCGAAAGGCGAGUGAGGUCU UGCGGGUG 6247
1298 CAGCCACU G CCGUCUGG 765 CCAGACGG GCCGAAAGGCGAGUGAGGUCU AGUGGCUG 6248
1301 CCACUGCC G UCUGGGCC 766 GGCCCAGA GCCGAAAGGCGAGUGAGGUCU GGCAGUGG 6249
1307 CCGUCUGG G CCAGGCAG 767 CUGCCUGG GCCGAAAGGCGAGUGAGGUCU CCAGACGG 6250
1312 UGGGCCAG G CAGGCAGC 768 GCUGCCUG GCCGAAAGGCGAGUGAGGUCU CUGGCCCA 6251
1316 CCAGGCAG G CAGCGGGG 769 CCCCGCUG GCCGAAAGGCGAGUGAGGUCU CUGCCUGG 6252
1319 GGCAGGCA G CGGGGGUG 770 CACCCCCG GCCGAAAGGCGAGUGAGGUCU UGCCUGCC 6253
1325 CAGCGGGG G UGGCGGGA 771 UCCCGCCA GCCGAAAGGCGAGUGAGGUCU CCCCGCUG 6254
1328 CGGGGGUG G CGGGACUG 772 CAGUCCCG GCCGAAAGGCGAGUGAGGUCU CACCCCCG 6255
1337 CGGGACUG G UGACUCAG 773 CUGAGUCA GCCGAAAGGCGAGUGAGGUCU CAGUCCCG 6256
1349 CUCAGAAG G CUCAGGUG 774 CACCUGAG GCCGAAAGGCGAGUGAGGUCU CUUCUGAG 6257
1355 AGGCUCAG G UGCCCUAC 775 GUAGGGCA GCCGAAAGGCGAGUGAGGUCU CUGAGCCU 6258
1357 GCUCAGGU G CCCUACCC 776 GGGUAGGG GCCGAAAGGCGAGUGAGGUCU ACCUGAGC 6259
1367 CCUACCCA G CCUCACCU 777 AGGUGAGG GCCGAAAGGCGAGUGAGGUCU UGGGUAGG 6260
1376 CCUCACCU G CAGCCUCA 778 UGAGGCUG GCCGAAAGGCGAGUGAGGUCU AGGUGAGG 6261
1379 CACCUGCA G CCUCACCC 779 GGGUGAGG GCCGAAAGGCGAGUGAGGUCU UGCAGGUG 6262
1394 CCCCCUGG G CCUGGCGC 780 GCGCCAGG GCCGAAAGGCGAGUGAGGUCU CCAGGGGG 6263
1399 UGGGCCUG G CGCUGGUG 781 CACCAGCG GCCGAAAGGCGAGUGAGGUCU CAGGCCCA 6264
1401 GGCCUGGC G CUGGUGCU 782 AGCACCAG GCCGAAAGGCGAGUGAGGUCU GCCAGGCC 6265
1405 UGGCGCUG G UGCUGUGG 783 CCACAGCA GCCGAAAGGCGAGUGAGGUCU CAGCGCCA 6266
1407 GCGCUGGU G CUGUGGAC 784 GUCCACAG GCCGAAAGGCGAGUGAGGUCU ACCAGCGC 6267
1410 CUGGUGCU G UGGACAGU 785 ACUGUCCA GCCGAAAGGCGAGUGAGGUCU AGCACCAG 6268
1417 UGUGGACA G UGCUUGGG 786 CCCAAGCA GCCGAAAGGCGAGUGAGGUCU UGUCCACA 6269
1419 UGGACAGU G CUUGGGCC 787 GGCCCAAG GCCGAAAGGCGAGUGAGGUCU ACUGUCCA 6270
1425 GUGCUUGG G CCCUGCUG 788 CAGCAGGG GCCGAAAGGCGAGUGAGGUCU CCAAGCAC 6271
1430 UGGGCCCU G CUGACCCC 789 GGGGUCAG GCCGAAAGGCGAGUGAGGUCU AGGGCCCA 6272
Input Sequence = AF283463. Cut Site = G/Y
Arm Length = 8. Core Sequence = GCcgaaagGCGaGuCaaGGuCu
AF283463 (Homo sapiens Nogo receptor mRNA, complete cds.; 1441 bp) Table VI: Human NOGO Receptor DNAzyme and Substrate Sequence
Pos Substrate Seq DNAzyme Seq ID ID
10 CAACCCCU A CGAUGAAG 1 CTTCATCG GGCTAGCTACAACGA AGGGGTTG 6273
108 GCCUGCGU A UGCUACAA 3 TTGTAGCA GGCTAGCTACAACGA ACGCAGGC 6274
113 CGUAUGCU A CAAUGAGC 4 GCTCATTG GGCTAGCTACAACGA AGCATACG 6275
408 GGCCGCCU A CACACGCU 26 AGCGTGTG GGCTAGCTACAACGA AGGCGGCC 6276
485 CCUGCAGU A CCUCUACC 29 GGTAGAGG GGCTAGCTACAACGA ACTGCAGG 6277
491 GUACCUCU A CCUGCAGG 31 CCTGCAGG GGCTAGCTACAACGA AGAGGTAC 6278
636 CGUCUCCU A CUGCACCA 45 TGGTGCAG GGCTAGCTACAACGA AGGAGACG 6279
707 GACACUCU A UCUGUUUG 51 CAAACAGA GGCTAGCTACAACGA AGAGTGTC 6280
726 AACAAUCU A UCAGCGCU 56 AGCGCTGA GGCTAGCTACAACGA AGATTGTT 6281
773 CCUGCAGU A CCUGAGGC 58 GCCTCAGG GGCTAGCTACAACGA ACTGCAGG 6282
959 CGGCCCUU A CCAUCCCA 70 TGGGATGG GGCTAGCTACAACGA AAGGGCCG 6283
1050 GCCUCAGU A CUGGAGCC 76 GGCTCCAG GGCTAGCTACAACGA ACTGAGGC 6284
1362 GGUGCCCU A CCCAGCCU 97 AGGCTGGG GGCTAGCTACAACGA AGGGCACC 6285
51 CUGCUGGC A UGGGUGCU 107 AGCACCCA GGCTAGCTACAACGA GCCAGCAG 6286
90 GCAGCCCC A UGCCCAGG 118 CCTGGGCA GGCTAGCTACAACGA GGGGCTGC 6287
175 CCGUGGGC A UCCCUGCU 143 AGCAGGGA GGCTAGCTACAACGA GCCCACGG 6288
196 GCCAGCGC A UCUUCCUG 152 CAGGAAGA GGCTAGCTACAACGA GCGCTGGC 6289
206 CUUCCUGC A CGGCAACC 156 GGTTGCCG GGCTAGCTACAACGA GCAGGAAG 6290
569 CUUCCUGC A CGGCAACC 156 GGTTGCCG GGCTAGCTACAACGA GCAGGAAG 6290
217 GCAACCGC A UCUCGCAU 159 ATGCGAGA GGCTAGCTACAACGA GCGGTTGC 6291
224 CAUCUCGC A UGUGCCAG 161 CTGGCACA GGCTAGCTACAACGA GCGAGATG 6292
262 GCAACCUC A CCAUCCUG 175 CAGGATGG GGCTAGCTACAACGA GAGGTTGC 6293
265 ACCUCACC A UCCUGUGG 177 CCACAGGA GGCTAGCTACAACGA GGTGAGGT 6294
278 GUGGCUGC A CUCGAAUG 181 CATTCGAG GGCTAGCTACAACGA GCAGCCAC 6295
316 CUGCCUUC A CUGGCCUG 189 CAGGCCAG GGCTAGCTACAACGA GAAGGCAG 6296
360 GAUAAUGC A CAGCUCCG 203 CGGAGCTG GGCTAGCTACAACGA GCATTATC 6297
385 ACCCUGCC A CAUUCCAC 212 GTGGAATG GGCTAGCTACAACGA GGCAGGGT 6298
387 CCUGCCAC A UUCCACGG 213 CCGTGGAA GGCTAGCTACAACGA GTGGCAGG 6299
392 CACAUUCC A CGGCCUGG 215 CCAGGCCG GGCTAGCTACAACGA GGAATGTG 6300
410 CCGCCUAC A CACGCUGC 221 GCAGCGTG GGCTAGCTACAACGA GTAGGCGG 6301
412 GCCUACAC A CGCUGCAC 222 GTGCAGCG GGCTAGCTACAACGA GTGTAGGC 6302
419 CACGCUGC A CCUGGACC 224 GGTCCAGG GGCTAGCTACAACGA GCAGCGTG 6303
516 CUGCAGGC A CUGCCUGA 253 TCAGGCAG GGCTAGCTACAACGA GCCTGCAG 6304
529 CUGAUGAC A CCUUCCGC 257 GCGGAAGG GGCTAGCTACAACGA GTCATCAG 6305
553 GCAACCUC A CACACCUC 266 GAGGTGTG GGCTAGCTACAACGA GAGGTTGC 6306
555 AACCUCAC A CACCUCUU 267 AAGAGGTG GGCTAGCTACAACGA GTGAGGTT 6307
557 CCUCACAC A CCUCUUCC 268 GGAAGAGG GGCTAGCTACAACGA GTGTGAGG 6308
580 GCAACCGC A UCUCCAGC 275 GCTGGAGA GGCTAGCTACAACGA GCGGTTGC 6309
617 UGGGCUGC A CAGCCUCG 285 CGAGGCTG GGCTAGCTACAACGA GCAGCCCA 6310
641 CCUACUGC A CCAGAACC 294 GGTTCTGG GGCTAGCTACAACGA GCAGTAGG 6311
659 CGUGGCCC A UGUGCACC 300 GGTGCACA GGCTAGCTACAACGA GGGCCACG 6312
665 CCAUGUGC A CCCGCAUG 301 CATGCGGG GGCTAGCTACAACGA GCACATGG 6313
671 GCACCCGC A UGCCUUCC 304 GGAAGGCA GGCTAGCTACAACGA GCGGGTGC 6314
697 GCCGCCUC A UGACACUC 313 GAGTGTCA GGCTAGCTACAACGA GAGGCGGC 6315
702 CUCAUGAC A CUCUAUCU 314 AGATAGAG GGCTAGCTACAACGA GTCATGAG 6316
739 CGCUGCCC A CUGAGGCC 326 GGCCTCAG GGCTAGCTACAACGA GGGCAGCG 6317
816 UGCCGGGC A CGCCCACU 352 AGTGGGCG GGCTAGCTACAACGA GCCCGGCA 6318 822 GCACGCCC A CUCUGGGC 355 GCCCAGAG GGCTAGCTACAACGA GGGCGTGC 6319
949 CUGUGGCC A CCGGCCCU 396 AGGGCCGG GGCTAGCTACAACGA GGCCACAG 6320
962 CCCUUACC A UCCCAUCU 402 AGATGGGA GGCTAGCTACAACGA GGTAAGGG 6321
967 ACCAUCCC A UCUGGACC 405 GGTCCAGA GGCTAGCTACAACGA GGGATGGT 6322
985 GCAGGGCC A CCGAUGAG 410 CTCATCGG GGCTAGCTACAACGA GGCCCTGC 6323
1140 UCUGGCCC A CGGCACAU 450 ATGTGCCG GGCTAGCTACAACGA GGGCCAGA 6324
1145 CCCACGGC A CAUCAAUG 451 CATTGATG GGCTAGCTACAACGA GCCGTGGG 6325
1147 CACGGCAC A UCAAUGAC 452 GTCATTGA GGCTAGCTACAACGA GTGCCGTG 6326
1158 AAUGACUC A CCCUUUGG 455 CCAAAGGG GGCTAGCTACAACGA GAGTCATT 6327
1198 CCCCGCUC A CUGCAGUG 471 CACTGCAG GGCTAGCTACAACGA GAGCGGGG 6328
1227 UCCGAGCC A CCAGGGUU 479 AACCCTGG GGCTAGCTACAACGA GGCTCGGA 6329
1240 GGUUCCCC A CCUCGGGC 485 GCCCGAGG GGCTAGCTACAACGA GGGGAACC 6330
1272 GGCUGUUC A CGCAAGAA 495 TTCTTGCG GGCTAGCTACAACGA GAACAGCC 6331
1285 AGAACCGC A CCCGCAGC 498 GCTGCGGG GGCTAGCTACAACGA GCGGTTCT 6332
1295 CCGCAGCC A CUGCCGUC 503 GACGGCAG GGCTAGCTACAACGA GGCTGCGG 6333
1372 CCAGCCUC A CCUGCAGC 524 GCTGCAGG GGCTAGCTACAACGA GAGGCTGG 6334
1384 GCAGCCUC A CCCCCCUG 530 CAGGGGGG GGCTAGCTACAACGA GAGGCTGC 6335
22 UGAAGAGG G CGUCCGCU 547 AGCGGACG GGCTAGCTACAACGA CCTCTTCA 6336
24 AAGAGGGC G UCCGCUGG 548 CCAGCGGA GGCTAGCTACAACGA GCCCTCTT 6337
28 GGGCGUCC G CUGGAGGG 549 CCCTCCAG GGCTAGCTACAACGA GGACGCCC 6338
38 UGGAGGGA G CCGGCUGC 550 GCAGCCGG GGCTAGCTACAACGA TCCCTCCA 6339
42 GGGAGCCG G CUGCUGGC 551 GCCAGCAG GGCTAGCTACAACGA CGGCTCCC 6340
45 AGCCGGCU G CUGGCAUG 552 CATGCCAG GGCTAGCTACAACGA AGCCGGCT 6341
49 GGCUGCUG G CAUGGGUG 553 CACCCATG GGCTAGCTACAACGA CAGCAGCC 6342
55 UGGCAUGG G UGCUGUGG 554 CCACAGCA GGCTAGCTACAACGA CCATGCCA 6343
57 GCAUGGGU G CUGUGGCU 555 AGCCACAG GGCTAGCTACAACGA ACCCATGC 6344
60 UGGGUGCU G UGGCUGCA 556 TGCAGCCA GGCTAGCTACAACGA AGCACCCA 6345
63 GUGCUGUG G CUGCAGGC 557 GCCTGCAG GGCTAGCTACAACGA CACAGCAC 6346
66 CUGUGGCU G CAGGCCUG 558 CAGGCCTG GGCTAGCTACAACGA AGCCACAG 6347
70 GGCUGCAG G CCUGGCAG 559 CTGCCAGG GGCTAGCTACAACGA CTGCAGCC 6348
75 CAGGCCUG G CAGGUGGC 560 GCCACCTG GGCTAGCTACAACGA CAGGCCTG 6349
79 CCUGGCAG G UGGCAGCC 561 GGCTGCCA GGCTAGCTACAACGA CTGCCAGG 6350
82 GGCAGGUG G CAGCCCCA 562 TGGGGCTG GGCTAGCTACAACGA CACCTGCC 6351
85 AGGUGGCA G CCCCAUGC 563 GCATGGGG GGCTAGCTACAACGA TGCCACCT 6352
92 AGCCCCAU G CCCAGGUG 564 CACCTGGG GGCTAGCTACAACGA ATGGGGCT 6353
98 AUGCCCAG G UGCCUGCG 565 CGCAGGCA GGCTAGCTACAACGA CTGGGCAT 6354
100 GCCCAGGU G CCUGCGUA 566 TACGCAGG GGCTAGCTACAACGA ACCTGGGC 6355
104 AGGUGCCU G CGUAUGCU 567 AGCATACG GGCTAGCTACAACGA AGGCACCT 6356
106 GUGCCUGC G UAUGCUAC 568 GTAGCATA GGCTAGCTACAACGA GCAGGCAC 6357
110 CUGCGUAU G CUACAAUG 569 CATTGTAG GGCTAGCTACAACGA ATACGCAG 6358
120 UACAAUGA G CCCAAGGU 570 ACCTTGGG GGCTAGCTACAACGA TCATTGTA 6359
127 AGCCCAAG G UGACGACA 571 TGTCGTCA GGCTAGCTACAACGA CTTGGGCT 6360
137 GACGACAA G CUGCCCCC 572 GGGGGCAG GGCTAGCTACAACGA TTGTCGTC 6361
140 GACAAGCU G CCCCCAGC 573 GCTGGGGG GGCTAGCTACAACGA AGCTTGTC 6362
147 UGCCCCCA G CAGGGCCU 574 AGGCCCTG GGCTAGCTACAACGA TGGGGGCA 6363
152 CCAGCAGG G CCUGCAGG 575 CCTGCAGG GGCTAGCTACAACGA CCTGCTGG 6364
156 CAGGGCCU G CAGGCUGU 576 ACAGCCTG GGCTAGCTACAACGA AGGCCCTG 6365
160 GCCUGCAG G CUGUGCCC 577 GGGCACAG GGCTAGCTACAACGA CTGCAGGC 6366
163 UGCAGGCU G UGCCCGUG 578 CACGGGCA GGCTAGCTACAACGA AGCCTGCA 6367
165 CAGGCUGU G CCCGUGGG 579 CCCACGGG GGCTAGCTACAACGA ACAGCCTG 6368
169 CUGUGCCC G UGGGCAUC 580 GATGCCCA GGCTAGCTACAACGA GGGCACAG 6369 173 GCCCGUGG G CAUCCCUG 581 CAGGGATG GGCTAGCTACAACGA CCACGGGC 6370
181 GCAUCCCU G CUGCCAGC 582 GCTGGCAG GGCTAGCTACAACGA AGGGATGC 6371
184 UCCCUGCU G CCAGCCAG 583 CTGGCTGG GGCTAGCTACAACGA AGCAGGGA 6372
188 UGCUGCCA G CCAGCGCA 584 TGCGCTGG GGCTAGCTACAACGA TGGCAGCA 6373
192 GCCAGCCA G CGCAUCUU 585 AAGATGCG GGCTAGCTACAACGA TGGCTGGC 6374
194 CAGCCAGC G CAUCUUCC 586 GGAAGATG GGCTAGCTACAACGA GCTGGCTG 6375
204 AUCUUCCU G CACGGCAA 587 TTGCCGTG GGCTAGCTACAACGA AGGAAGAT 6376
209 CCUGCACG G CAACCGCA 588 TGCGGTTG GGCTAGCTACAACGA CGTGCAGG 6377
572 CCUGCACG G CAACCGCA 588 TGCGGTTG GGCTAGCTACAACGA CGTGCAGG 6377
215 CGGCAACC G CAUCUCGC 589 GCGAGATG GGCTAGCTACAACGA GGTTGCCG 6378
222 CGCAUCUC G CAUGUGCC 590 GGCACATG GGCTAGCTACAACGA GAGATGCG 6379
226 UCUCGCAU G UGCCAGCU 591 AGCTGGCA GGCTAGCTACAACGA ATGCGAGA 6380
228 UCGCAUGU G CCAGCUGC 592 GCAGCTGG GGCTAGCTACAACGA ACATGCGA 6381
232 AUGUGCCA G CUGCCAGC 593 GCTGGCAG GGCTAGCTACAACGA TGGCACAT 6382
235 UGCCAGCU G CCAGCUUC 594 GAAGCTGG GGCTAGCTACAACGA AGCTGGCA 6383
239 AGCUGCCA G CUUCCGUG 595 CACGGAAG GGCTAGCTACAACGA TGGCAGCT 6384
245 CAGCUUCC G UGCCUGCC 596 GGCAGGCA GGCTAGCTACAACGA GGAAGCTG 6385
247 GCUUCCGU G CCUGCCGC 597 GCGGCAGG GGCTAGCTACAACGA ACGGAAGC 6386
251 CCGUGCCU G CCGCAACC 598 GGTTGCGG GGCTAGCTACAACGA AGGCACGG 6387
254 UGCCUGCC G CAACCUCA 599 TGAGGTTG GGCTAGCTACAACGA GGCAGGCA 6388
270 ACCAUCCU G UGGCUGCA 600 TGCAGCCA GGCTAGCTACAACGA AGGATGGT 6389
273 AUCCUGUG G CUGCACUC 601 GAGTGCAG GGCTAGCTACAACGA CACAGGAT 6390
276 CUGUGGCU G CACUCGAA 602 TTCGAGTG GGCTAGCTACAACGA AGCCACAG 6391
286 ACUCGAAU G UGCUGGCC 603 GGCCAGCA GGCTAGCTACAACGA ATTCGAGT 6392
288 UCGAAUGU G CUGGCCCG 604 CGGGCCAG GGCTAGCTACAACGA ACATTCGA 6393
292 AUGUGCUG G CCCGAAUU 605 AATTCGGG GGCTAGCTACAACGA CAGCACAT 6394
304 GAAUUGAU G CGGCUGCC 606 GGCAGCCG GGCTAGCTACAACGA ATCAATTC 6395
307 UUGAUGCG G CUGCCUUC 607 GAAGGCAG GGCTAGCTACAACGA CGCATCAA 6396
310 AUGCGGCU G CCUUCACU 608 AGTGAAGG GGCTAGCTACAACGA AGCCGCAT 6397
320 CUUCACUG G CCUGGCCC 609 GGGCCAGG GGCTAGCTACAACGA CAGTGAAG 6398
325 CUGGCCUG G CCCUCCUG 610 CAGGAGGG GGCTAGCTACAACGA CAGGCCAG 6399
336 CUCCUGGA G CAGCUGGA 611 TCCAGCTG GGCTAGCTACAACGA TCCAGGAG 6400
339 CUGGAGCA G CUGGACCU 612 AGGTCCAG GGCTAGCTACAACGA TGCTCCAG 6401
350 GGACCUCA G CGAUAAUG 613 CATTATCG GGCTAGCTACAACGA TGAGGTCC 6402
358 GCGAUAAU G CACAGCUC 614 GAGCTGTG GGCTAGCTACAACGA ATTATCGC 6403
363 AAUGCACA G CUCCGGUC 615 GACCGGAG GGCTAGCTACAACGA TGTGCATT 6404
369 CAGCUCCG G UCUGUGGA 616 TCCACAGA GGCTAGCTACAACGA CGGAGCTG 6405
373 UCCGGUCU G UGGACCCU 617 AGGGTCCA GGCTAGCTACAACGA AGACCGGA 6406
382 UGGACCCU G CCACAUUC 618 GAATGTGG GGCTAGCTACAACGA AGGGTCCA 6407
395 AUUCCACG G CCUGGGCC 619 GGCCCAGG GGCTAGCTACAACGA CGTGGAAT 6408
401 CGGCCUGG G CCGCCUAC 620 GTAGGCGG GGCTAGCTACAACGA CCAGGCCG 6409
404 CCUGGGCC G CCUACACA 621 TGTGTAGG GGCTAGCTACAACGA GGCCCAGG 6410
414 CUACACAC G CUGCACCU 622 AGGTGCAG GGCTAGCTACAACGA GTGTGTAG 6411
417 CACACGCU G CACCUGGA 623 TCCAGGTG GGCTAGCTACAACGA AGCGTGTG 6412
428 CCUGGACC G CUGCGGCC 624 GGCCGCAG GGCTAGCTACAACGA GGTCCAGG 6413
431 GGACCGCU G CGGCCUGC 625 GCAGGCCG GGCTAGCTACAACGA AGCGGTCC 6414
434 CCGCUGCG G CCUGCAGG 626 CCTGCAGG GGCTAGCTACAACGA CGCAGCGG 6415
438 UGCGGCCU G CAGGAGCU 627 AGCTCCTG GGCTAGCTACAACGA AGGCCGCA 6416
444 CUGCAGGA G CUGGGCCC 628 GGGCCCAG GGCTAGCTACAACGA TCCTGCAG 6417
449 GGAGCUGG G CCCGGGGC 629 GCCCCGGG GGCTAGCTACAACGA CCAGCTCC 6418
456 GGCCCGGG G CUGUUCCG 630 CGGAACAG GGCTAGCTACAACGA CCCGGGCC 6419 459 CCGGGGCU G UUCCGCGG 631 CCGCGGAA GGCTAGCTACAACGA AGCCCCGG 6420
464 GCUGUUCC G CGGCCUGG 632 CCAGGCCG GGCTAGCTACAACGA GGAACAGC 6421
467 GUUCCGCG G CCUGGCUG 633 CAGCCAGG GGCTAGCTACAACGA CGCGGAAC 6422
472 GCGGCCUG G CUGCCCUG 634 CAGGGCAG GGCTAGCTACAACGA CAGGCCGC 6423
475 GCCUGGCU G CCCUGCAG 635 CTGCAGGG GGCTAGCTACAACGA AGCCAGGC 6424
480 GCUGCCCU G CAGUACCU 636 AGGTACTG GGCTAGCTACAACGA AGGGCAGC 6425
483 GCCCUGCA G UACCUCUA 637 TAGAGGTA GGCTAGCTACAACGA TGCAGGGC 6426
495 CUCUACCU G CAGGACAA 638 TTGTCCTG GGCTAGCTACAACGA AGGTAGAG 6427
505 AGGACAAC G CGCUGCAG 639 CTGCAGCG GGCTAGCTACAACGA GTTGTCCT 6428
507 GACAACGC G CUGCAGGC 640 GCCTGCAG GGCTAGCTACAACGA GCGTTGTC 6429
510 AACGCGCU G CAGGCACU 641 AGTGCCTG GGCTAGCTACAACGA AGCGCGTT 6430
514 CGCUGCAG G CACUGCCU 642 AGGCAGTG GGCTAGCTACAACGA CTGCAGCG 6431
519 CAGGCACU G CCUGAUGA 643 TCATCAGG GGCTAGCTACAACGA AGTGCCTG 6432
536 CACCUUCC G CGACCUGG 644 CCAGGTCG GGCTAGCTACAACGA GGAAGGTG 6433
545 CGACCUGG G CAACCUCA 645 TGAGGTTG GGCTAGCTACAACGA CCAGGTCG 6434
567 CUCUUCCU G CACGGCAA 646 TTGCCGTG GGCTAGCTACAACGA AGGAAGAG 6435
578 CGGCAACC G CAUCUCCA 647 TGGAGATG GGCTAGCTACAACGA GGTTGCCG 6436
587 CAUCUCCA G CGUGCCCG 648 CGGGCACG GGCTAGCTACAACGA TGGAGATG 6437
589 UCUCCAGC G UGCCCGAG 649 CTCGGGCA GGCTAGCTACAACGA GCTGGAGA 6438
591 UCCAGCGU G CCCGAGCG 650 CGCTCGGG GGCTAGCTACAACGA ACGCTGGA 6439
597 GUGCCCGA G CGCGCCUU 651 AAGGCGCG GGCTAGCTACAACGA TCGGGCAC 6440
599 GCCCGAGC G CGCCUUCC 652 GGAAGGCG GGCTAGCTACAACGA GCTCGGGC 6441
601 CCGAGCGC G CCUUCCGU 653 ACGGAAGG GGCTAGCTACAACGA GCGCTCGG 6442
608 CGCCUUCC G UGGGCUGC 654 GCAGCCCA GGCTAGCTACAACGA GGAAGGCG 6443
612 UUCCGUGG G CUGCACAG 655 CTGTGCAG GGCTAGCTACAACGA CCACGGAA 6444
615 CGUGGGCU G CACAGCCU 656 AGGCTGTG GGCTAGCTACAACGA AGCCCACG 6445
620 GCUGCACA G CCUCGACC 657 GGTCGAGG GGCTAGCTACAACGA TGTGCAGC 6446
629 CCUCGACC G UCUCCUAC 658 GTAGGAGA GGCTAGCTACAACGA GGTCGAGG 6447
639 CUCCUACU G CACCAGAA 659 TTCTGGTG GGCTAGCTACAACGA AGTAGGAG 6448
650 CCAGAACC G CGUGGCCC 660 GGGCCACG GGCTAGCTACAACGA GGTTCTGG 6449
652 AGAACCGC G UGGCCCAU 661 ATGGGCCA GGCTAGCTACAACGA GCGGTTCT 6450
655 ACCGCGUG G CCCAUGUG 662 CACATGGG GGCTAGCTACAACGA CACGCGGT 6451
661 UGGCCCAU G UGCACCCG 663 CGGGTGCA GGCTAGCTACAACGA ATGGGCCA 6452
663 GCCCAUGU G CACCCGCA 664 TGCGGGTG GGCTAGCTACAACGA ACATGGGC 6453
669 GUGCACCC G CAUGCCUU 665 AAGGCATG GGCTAGCTACAACGA GGGTGCAC 6454
673 ACCCGCAU G CCUUCCGU 666 ACGGAAGG GGCTAGCTACAACGA ATGCGGGT 6455
680 UGCCUUCC G UGACCUUG 667 CAAGGTCA GGCTAGCTACAACGA GGAAGGCA 6456
689 UGACCUUG G CCGCCUCA 668 TGAGGCGG GGCTAGCTACAACGA CAAGGTCA 6457
692 CCUUGGCC G CCUCAUGA 669 TCATGAGG GGCTAGCTACAACGA GGCCAAGG 6458
711 CUCUAUCU G UUUGCCAA 670 TTGGCAAA GGCTAGCTACAACGA AGATAGAG 6459
715 AUCUGUUU G CCAACAAU 671 ATTGTTGG GGCTAGCTACAACGA AAACAGAT 6460
730 AUCUAUCA G CGCUGCCC 672 GGGCAGCG GGCTAGCTACAACGA TGATAGAT 6461
732 CUAUCAGC G CUGCCCAC 673 GTGGGCAG GGCTAGCTACAACGA GCTGATAG 6462
735 UCAGCGCU G CCCACUGA 674 TCAGTGGG GGCTAGCTACAACGA AGCGCTGA 6463
745 CCACUGAG G CCCUGGCC 675 GGCCAGGG GGCTAGCTACAACGA CTCAGTGG 6464
751 AGGCCCUG G CCCCCCUG 676 CAGGGGGG GGCTAGCTACAACGA CAGGGCCT 6465
759 GCCCCCCU G CGUGCCCU 677 AGGGCACG GGCTAGCTACAACGA AGGGGGGC 6466
761 CCCCCUGC G UGCCCUGC 678 GCAGGGCA GGCTAGCTACAACGA GCAGGGGG 6467
763 CCCUGCGU G CCCUGCAG 679 CTGCAGGG GGCTAGCTACAACGA ACGCAGGG 6468
768 CGUGCCCU G CAGUACCU 680 AGGTACTG GGCTAGCTACAACGA AGGGCACG 6469
771 GCCCUGCA G UACCUGAG 681 CTCAGGTA GGCTAGCTACAACGA TGCAGGGC 6470 780 UACCUGAG G CUCAACGA 682 TCGTTGAG GGCTAGCTACAACGA CTCAGGTA 6471
799 ACCCCUGG G UGUGUGAC 683 GTCACACA GGCTAGCTACAACGA CCAGGGGT 6472
801 CCCUGGGU G UGUGACUG 684 CAGTCACA GGCTAGCTACAACGA ACCCAGGG 6473
803 CUGGGUGU G UGACUGCC 685 GGCAGTCA GGCTAGCTACAACGA ACACCCAG 6474
809 GUGUGACU G CCGGGCAC 686 GTGCCCGG GGCTAGCTACAACGA AGTCACAC 6475
814 ACUGCCGG G CACGCCCA 687 TGGGCGTG GGCTAGCTACAACGA CCGGCAGT 6476
818 CCGGGCAC G CCCACUCU 688 AGAGTGGG GGCTAGCTACAACGA GTGCCCGG 6477
829 CACUCUGG G CCUGGCUG 689 CAGCCAGG GGCTAGCTACAACGA CCAGAGTG 6478
834 UGGGCCUG G CUGCAGAA 690 TTCTGCAG GGCTAGCTACAACGA CAGGCCCA 6479
837 GCCUGGCU G CAGAAGUU 691 AACTTCTG GGCTAGCTACAACGA AGCCAGGC 6480
843 CUGCAGAA G UUCCGCGG 692 CCGCGGAA GGCTAGCTACAACGA TTCTGCAG 6481
848 GAAGUUCC G CGGCUCCU 693 AGGAGCCG GGCTAGCTACAACGA GGAACTTC 6482
851 GUUCCGCG G CUCCUCCU 694 AGGAGGAG GGCTAGCTACAACGA CGCGGAAC 6483
865 CCUCCGAG G UGCCCUGC 695 GCAGGGCA GGCTAGCTACAACGA CTCGGAGG 6484
867 UCCGAGGU G CCCUGCAG 696 CTGCAGGG GGCTAGCTACAACGA ACCTCGGA 6485
872 GGUGCCCU G CAGCCUCC 697 GGAGGCTG GGCTAGCTACAACGA AGGGCACC 6486
875 GCCCUGCA G CCUCCCGC 698 GCGGGAGG GGCTAGCTACAACGA TGCAGGGC 6487
882 AGCCUCCC G CAACGCCU 699 AGGCGTTG GGCTAGCTACAACGA GGGAGGCT 6488
887 CCCGCAAC G CCUGGCUG 700 CAGCCAGG GGCTAGCTACAACGA GTTGCGGG 6489
892 AACGCCUG G CUGGCCGU 701 ACGGCCAG GGCTAGCTACAACGA CAGGCGTT 6490
896 CCUGGCUG G CCGUGACC 702 GGTCACGG GGCTAGCTACAACGA CAGCCAGG 6491
899 GGCUGGCC G UGACCUCA 703 TGAGGTCA GGCTAGCTACAACGA GGCCAGCC 6492
911 CCUCAAAC G CCUAGCUG 704 CAGCTAGG GGCTAGCTACAACGA GTTTGAGG 6493
916 AACGCCUA G CUGCCAAU 705 ATTGGCAG GGCTAGCTACAACGA TAGGCGTT 6494
919 GCCUAGCU G CCAAUGAC 706 GTCATTGG GGCTAGCTACAACGA AGCTAGGC 6495
930 AAUGACCU G CAGGGCUG 707 CAGCCCTG GGCTAGCTACAACGA AGGTCATT 6496
935 CCUGCAGG G CUGCGCUG 708 CAGCGCAG GGCTAGCTACAACGA CCTGCAGG 6497
938 GCAGGGCU G CGCUGUGG 709 CCACAGCG GGCTAGCTACAACGA AGCCCTGC 6498
940 AGGGCUGC G CUGUGGCC 710 GGCCACAG GGCTAGCTACAACGA GCAGCCCT 6499
943 GCUGCGCU G UGGCCACC 711 GGTGGCCA GGCTAGCTACAACGA AGCGCAGC 6500
946 GCGCUGUG G CCACCGGC 712 GCCGGTGG GGCTAGCTACAACGA CACAGCGC 6501
953 GGCCACCG G CCCUUACC 713 GGTAAGGG GGCTAGCTACAACGA CGGTGGCC 6502
977 CUGGACCG G CAGGGCCA 714 TGGCCCTG GGCTAGCTACAACGA CGGTCCAG 6503
982 CCGGCAGG G CCACCGAU 715 ATCGGTGG GGCTAGCTACAACGA CCTGCCGG 6504
996 GAUGAGGA G CCGCUGGG 716 CCCAGCGG GGCTAGCTACAACGA TCCTCATC 6505
999 GAGGAGCC G CUGGGGCU 717 AGCCCCAG GGCTAGCTACAACGA GGCTCCTC 6506
1005 CCGCUGGG G CUUCCCAA 718 TTGGGAAG GGCTAGCTACAACGA CCCAGCGG 6507
1014 CUUCCCAA G UGCUGCCA 719 TGGCAGCA GGCTAGCTACAACGA TTGGGAAG 6508
1016 UCCCAAGU G CUGCCAGC 720 GCTGGCAG GGCTAGCTACAACGA ACTTGGGA 6509
1019 CAAGUGCU G CCAGCCAG 721 CTGGCTGG GGCTAGCTACAACGA AGCACTTG 6510
1023 UGCUGCCA G CCAGAUGC 722 GCATCTGG GGCTAGCTACAACGA TGGCAGCA 6511
1030 AGCCAGAU G CCGCUGAC 723 GTCAGCGG GGCTAGCTACAACGA ATCTGGCT 6512
1033 CAGAUGCC G CUGACAAG 724 CTTGTCAG GGCTAGCTACAACGA GGCATCTG 6513
1042 CUGACAAG G CCUCAGUA 725 TACTGAGG GGCTAGCTACAACGA CTTGTCAG 6514
1048 AGGCCUCA G UACUGGAG 726 CTCCAGTA GGCTAGCTACAACGA TGAGGCCT 6515
1056 GUACUGGA G CCUGGAAG 727 CTTCCAGG GGCTAGCTACAACGA TCCAGTAC 6516
1069 GAAGACCA G CUUCGGCA 728 TGCCGAAG GGCTAGCTACAACGA TGGTCTTC 6517
1075 CAGCUUCG G CAGGCAAU 729 ATTGCCTG GGCTAGCTACAACGA CGAAGCTG 6518
1079 UUCGGCAG G CAAUGCGC 730 GCGCATTG GGCTAGCTACAACGA CTGCCGAA 6519
1084 CAGGCAAU G CGCUGAAG 731 CTTCAGCG GGCTAGCTACAACGA ATTGCCTG 6520
1086 GGCAAUGC G CUGAAGGG 732 CCCTTCAG GGCTAGCTACAACGA GCATTGCC 6521 1097 GAAGGGAC G CGUGCCGC 733 GCGGCACG GGCTAGCTACAACGA GTCCCTTC 6522
1099 AGGGACGC G UGCCGCCC 734 GGGCGGCA GGCTAGCTACAACGA GCGTCCCT 6523
1101 GGACGCGU G CCGCCCGG 735 CCGGGCGG GGCTAGCTACAACGA ACGCGTCC 6524
1104 CGCGUGCC G CCCGGUGA 736 TCACCGGG GGCTAGCTACAACGA GGCACGCG 6525
1109 GCCGCCCG G UGACAGCC 737 GGCTGTCA GGCTAGCTACAACGA CGGGCGGC 6526
1115 CGGUGACA G CCCGCCGG 738 CCGGCGGG GGCTAGCTACAACGA TGTCACCG 6527
1119 GACAGCCC G CCGGGCAA 739 TTGCCCGG GGCTAGCTACAACGA GGGCTGTC 6528
1124 CCCGCCGG G CAACGGCU 740 AGCCGTTG GGCTAGCTACAACGA CCGGCGGG 6529
1130 GGGCAACG G CUCUGGCC 741 GGCCAGAG GGCTAGCTACAACGA CGTTGCCC 6530
1136 CGGCUCUG G CCCACGGC 742 GCCGTGGG GGCTAGCTACAACGA CAGAGCCG 6531
1143 GGCCCACG G CACAUCAA 743 TTGATGTG GGCTAGCTACAACGA CGTGGGCC 6532
1173 GGGACUCU G CCUGGCUC 744 GAGCCAGG GGCTAGCTACAACGA AGAGTCCC 6533
1178 UCUGCCUG G CUCUGCUG 745 CAGCAGAG GGCTAGCTACAACGA CAGGCAGA 6534
1183 CUGGCUCU G CUGAGCCC 746 GGGCTCAG GGCTAGCTACAACGA AGAGCCAG 6535
1188 UCUGCUGA G CCCCCGCU 747 AGCGGGGG GGCTAGCTACAACGA TCAGCAGA 6536
1194 GAGCCCCC G CUCACUGC 748 GCAGTGAG GGCTAGCTACAACGA GGGGGCTC 6537
1201 CGCUCACU G CAGUGCGG 749 CCGCACTG GGCTAGCTACAACGA AGTGAGCG 6538
1204 UCACUGCA G UGCGGCCC 750 GGGCCGCA GGCTAGCTACAACGA TGCAGTGA 6539
1206 ACUGCAGU G CGGCCCGA 751 TCGGGCCG GGCTAGCTACAACGA ACTGCAGT 6540
1209 GCAGUGCG G CCCGAGGG 752 CCCTCGGG GGCTAGCTACAACGA CGCACTGC 6541
1217 GCCCGAGG G CUCCGAGC 753 GCTCGGAG GGCTAGCTACAACGA CCTCGGGC 6542
1224 GGCUCCGA G CCACCAGG 754 CCTGGTGG GGCTAGCTACAACGA TCGGAGCC 6543
1233 CCACCAGG G UUCCCCAC 755 GTGGGGAA GGCTAGCTACAACGA CCTGGTGG 6544
1247 CACCUCGG G CCCUCGCC 756 GGCGAGGG GGCTAGCTACAACGA CCGAGGTG 6545
1253 GGGCCCUC G CCGGAGGC 757 GCCTCCGG GGCTAGCTACAACGA GAGGGCCC 6546
1260 CGCCGGAG G CCAGGCUG 758 CAGCCTGG GGCTAGCTACAACGA CTCCGGCG 6547
1265 GAGGCCAG G CUGUUCAC 759 GTGAACAG GGCTAGCTACAACGA CTGGCCTC 6548
1268 GCCAGGCU G UUCACGCA 760 TGCGTGAA GGCTAGCTACAACGA AGCCTGGC 65 9
1274 CUGUUCAC G CAAGAACC 761 GGTTCTTG GGCTAGCTACAACGA GTGAACAG 6550
1283 CAAGAACC G CACCCGCA 762 TGCGGGTG GGCTAGCTACAACGA GGTTCTTG 6551
1289 CCGCACCC G CAGCCACU 763 AGTGGCTG GGCTAGCTACAACGA GGGTGCGG 6552
1292 CACCCGCA G CCACUGCC 764 GGCAGTGG GGCTAGCTACAACGA TGCGGGTG 6553
1298 CAGCCACU G CCGUCUGG 765 CCAGACGG GGCTAGCTACAACGA AGTGGCTG 6554
1301 CCACUGCC G UCUGGGCC 766 GGCCCAGA GGCTAGCTACAACGA GGCAGTGG 6555
1307 CCGUCUGG G CCAGGCAG 767 CTGCCTGG GGCTAGCTACAACGA CCAGACGG 6556
1312 UGGGCCAG G CAGGCAGC 768 GCTGCCTG GGCTAGCTACAACGA CTGGCCCA 6557
1316 CCAGGCAG G CAGCGGGG 769 CCCCGCTG GGCTAGCTACAACGA CTGCCTGG 6558
1319 GGCAGGCA G CGGGGGUG 770 CACCCCCG GGCTAGCTACAACGA TGCCTGCC 6559
1325 CAGCGGGG G UGGCGGGA 771 TCCCGCCA GGCTAGCTACAACGA CCCCGCTG 6560
1328 CGGGGGUG G CGGGACUG 772 CAGTCCCG GGCTAGCTACAACGA CACCCCCG 6561
1337 CGGGACUG G UGACUCAG 773 CTGAGTCA GGCTAGCTACAACGA CAGTCCCG 6562
1349 CUCAGAAG G CUCAGGUG 774 CACCTGAG GGCTAGCTACAACGA CTTCTGAG 6563
1355 AGGCUCAG G UGCCCUAC 775 GTAGGGCA GGCTAGCTACAACGA CTGAGCCT 6564
1357 GCUCAGGU G CCCUACCC 776 GGGTAGGG GGCTAGCTACAACGA ACCTGAGC 6565
1367 CCUACCCA G CCUCACCU 777 AGGTGAGG GGCTAGCTACAACGA TGGGTAGG 6566
1376 CCUCACCU G CAGCCUCA 778 TGAGGCTG GGCTAGCTACAACGA AGGTGAGG 6567
1379 CACCUGCA G CCUCACCC 779 GGGTGAGG GGCTAGCTACAACGA TGCAGGTG 6568
1394 CCCCCUGG G CCUGGCGC 780 GCGCCAGG GGCTAGCTACAACGA CCAGGGGG 6569
1399 UGGGCCUG G CGCUGGUG 781 CACCAGCG GGCTAGCTACAACGA CAGGCCCA 6570
1401 GGCCUGGC G CUGGUGCU 782 AGCACCAG GGCTAGCTACAACGA GCCAGGCC 6571
1405 UGGCGCUG G UGCUGUGG 783 CCACAGCA GGCTAGCTACAACGA CAGCGCCA 6572 1407 GCGCUGGU G CUGUGGAC 784 GTCCACAG GGCTAGCTACAACGA ACCAGCGC 6573
1410 CUGGUGCU G UGGACAGU 785 ACTGTCCA GGCTAGCTACAACGA AGCACCAG 6574
1417 UGUGGACA G UGCUUGGG 786 CCCAAGCA GGCTAGCTACAACGA TGTCCACA 6575
1419 UGGACAGU G CUUGGGCC 787 GGCCCAAG GGCTAGCTACAACGA ACTGTCCA 6576
1425 GUGCUUGG G CCCUGCUG 788 CAGCAGGG GGCTAGCTACAACGA CCAAGCAC 6577
1430 UGGGCCCU G CUGACCCC 789 GGGGTCAG GGCTAGCTACAACGA AGGGCCCA 6578
13 CCCCUACG A UGAAGAGG 790 CCTCTTCA GGCTAGCTACAACGA CGTAGGGG 6579
116 AUGCUACA A UGAGCCCA 791 TGGGCTCA GGCTAGCTACAACGA TGTAGCAT 6580
130 CCAAGGUG A CGACAAGC 792 GCTTGTCG GGCTAGCTACAACGA CACCTTGG 6581
133 AGGUGACG A CAAGCUGC 793 GCAGCTTG GGCTAGCTACAACGA CGTCACCT 6582
212 GCACGGCA A CCGCAUCU 794 AGATGCGG GGCTAGCTACAACGA TGCCGTGC 6583
575 GCACGGCA A CCGCAUCU 794 AGATGCGG GGCTAGCTACAACGA TGCCGTGC 6583
257 CUGCCGCA A CCUCACCA 795 TGGTGAGG GGCTAGCTACAACGA TGCGGCAG 6584
284 GCACUCGA A UGUGCUGG 796 CCAGCACA GGCTAGCTACAACGA TCGAGTGC 6585
298 UGGCCCGA A UUGAUGCG 797 CGCATCAA GGCTAGCTACAACGA TCGGGCCA 6586
302 CCGAAUUG A UGCGGCUG 798 CAGCCGCA GGCTAGCTACAACGA CAATTCGG 6587
344 GCAGCUGG A CCUCAGCG 799 CGCTGAGG GGCTAGCTACAACGA CCAGCTGC 6588
353 CCUCAGCG A UAAUGCAC 800 GTGCATTA GGCTAGCTACAACGA CGCTGAGG 6589
356 CAGCGAUA A UGCACAGC 801 GCTGTGCA GGCTAGCTACAACGA TATCGCTG 6590
377 GUCUGUGG A CCCUGCCA 802 TGGCAGGG GGCTAGCTACAACGA CCACAGAC 6591
425 GCACCUGG A CCGCUGCG 803 CGCAGCGG GGCTAGCTACAACGA CCAGGTGC 6592
500 CCUGCAGG A CAACGCGC 804 GCGCGTTG GGCTAGCTACAACGA CCTGCAGG 6593
503 GCAGGACA A CGCGCUGC 805 GCAGCGCG GGCTAGCTACAACGA TGTCCTGC 6594
524 ACUGCCUG A UGACACCU 806 AGGTGTCA GGCTAGCTACAACGA CAGGCAGT 6595
527 GCCUGAUG A CACCUUCC 807 GGAAGGTG GGCTAGCTACAACGA CATCAGGC 6596
539 CUUCCGCG A CCUGGGCA 808 TGCCCAGG GGCTAGCTACAACGA CGCGGAAG 6597
548 CCUGGGCA A CCUCACAC 809 GTGTGAGG GGCTAGCTACAACGA TGCCCAGG 6598
626 CAGCCUCG A CCGUCUCC 810 GGAGACGG GGCTAGCTACAACGA CGAGGCTG 6599
647 GCACCAGA A CCGCGUGG 811 CCACGCGG GGCTAGCTACAACGA TCTGGTGC 6600
683 CUUCCGUG A CCUUGGCC 812 GGCCAAGG GGCTAGCTACAACGA CACGGAAG 6601
700 GCCUCAUG A CACUCUAU 813 ATAGAGTG GGCTAGCTACAACGA CATGAGGC 6602
719 GUUUGCCA A CAAUCUAU 814 ATAGATTG GGCTAGCTACAACGA TGGCAAAC 6603
722 UGCCAACA A UCUAUCAG 815 CTGATAGA GGCTAGCTACAACGA TGTTGGCA 6604
785 GAGGCUCA A CGACAACC 816 GGTTGTCG GGCTAGCTACAACGA TGAGCCTC 6605
788 GCUCAACG A CAACCCCU 817 AGGGGTTG GGCTAGCTACAACGA CGTTGAGC 6606
791 CAACGACA A CCCCUGGG 818 CCCAGGGG GGCTAGCTACAACGA TGTCGTTG 6607
806 GGUGUGUG A CUGCCGGG 819 CCCGGCAG GGCTAGCTACAACGA CACACACC 6608
885 CUCCCGCA A CGCCUGGC 820 GCCAGGCG GGCTAGCTACAACGA TGCGGGAG 6609
902 UGGCCGUG A CCUCAAAC 821 GTTTGAGG GGCTAGCTACAACGA CACGGCCA 6610
909 GACCUCAA A CGCCUAGC 822 GCTAGGCG GGCTAGCTACAACGA TTGAGGTC 6611
923 AGCUGCCA A UGACCUGC 823 GCAGGTCA GGCTAGCTACAACGA TGGCAGCT 6612
926 UGCCAAUG A CCUGCAGG 824 CCTGCAGG GGCTAGCTACAACGA CATTGGCA 6613
973 CCAUCUGG A CCGGCAGG 825 CCTGCCGG GGCTAGCTACAACGA CCAGATGG 6614
989 GGCCACCG A UGAGGAGC 826 GCTCCTCA GGCTAGCTACAACGA CGGTGGCC 6615
1028 CCAGCCAG A UGCCGCUG 827 CAGCGGCA GGCTAGCTACAACGA CTGGCTGG 6616
1037 UGCCGCUG A CAAGGCCU 828 AGGCCTTG GGCTAGCTACAACGA CAGCGGCA 6617
1065 CCUGGAAG A CCAGCUUC 829 GAAGCTGG GGCTAGCTACAACGA CTTCCAGG 6618
1082 GGCAGGCA A UGCGCUGA 830 TCAGCGCA GGCTAGCTACAACGA TGCCTGCC 6619
1095 CUGAAGGG A CGCGUGCC 831 GGCACGCG GGCTAGCTACAACGA CCCTTCAG 6620
1112 GCCCGGUG A CAGCCCGC 832 GCGGGCTG GGCTAGCTACAACGA CACCGGGC 6621
1127 GCCGGGCA A CGGCUCUG 833 CAGAGCCG GGCTAGCTACAACGA TGCCCGGC 6622
Figure imgf000123_0001
Input Sequence = AF283463. Cut Site = R/Y
Arm Length = 8. Core Sequence = GGCTAGCTACAACGA
AF283463 (Homo sapiens Nogo receptor mRNA, complete cds.; 1441 bp)
Table VII: Human NOGO Receptor Amberzyme and Substrate Sequence
Pos Substrate Seq Amberzyme Rz Seq
ID ID
22 UGAAGAGG G CGUCCGCU 547 AGCGGACG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCUCUUCA 6630
24 AAGAGGGC G UCCGCUGG 548 CCAGCGGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCCCUCUU 6631
Figure imgf000124_0001
28 GGGCGUCC G CUGGAGGG 549 CCCUCCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGACGCCC 6632
38 UGGAGGGA G CCGGCUGC 550 GCAGCCGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCCUCCA 6633
42 GGGAGCCG G CUGCUGGC 551 GCCAGCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGGCUCCC 6634
45 AGCCGGCU G CUGGCAUG 552 CAUGCCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCCGGCU 6635
49 GGCUGCUG G CAUGGGUG 553 CACCCAUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGCAGCC 6636
55 UGGCAUGG G UGCUGUGG 554 CCACAGCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCAUGCCA 6637
57 GCAUGGGU G CUGUGGCU 555 AGCCACAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACCCAUGC 6638
60 UGGGUGCU G UGGCUGCA 556 UGCAGCCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCACCCA 6639
63 GUGCUGUG G CUGCAGGC 557 GCCUGCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CACAGCAC 6640
66 CUGUGGCU G CAGGCCUG 558 CAGGCCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCCACAG 6641
70 GGCUGCAG G CCUGGCAG 559 CUGCCAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGCAGCC 6642
75 CAGGCCUG G CAGGUGGC 560 GCCACCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGGCCUG 6643
79 CCUGGCAG G UGGCAGCC 561 GGCUGCCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUGCCAGG 6644
82 GGCAGGUG G CAGCCCCA 562 UGGGGCUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CACCUGCC 6645
85 AGGUGGCA G CCCCAUGC 563 GCAUGGGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGCCACCU 6646
92 AGCCCCAU G CCCAGGUG 564 CACCUGGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUGGGGCU 6647
98 AUGCCCAG G UGCCUGCG 565 CGCAGGCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUGGGCAU 6648
100 GCCCAGGU G CCUGCGUA 566 UACGCAGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACCUGGGC 6649
104 AGGUGCCU G CGUAUGCU 567 AGCAUACG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGCACCU 6650
106 GUGCCUGC G UAUGCUAC 568 GUAGCAUA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCAGGCAC 6651
110 CUGCGUAU G CUACAAUG 569 CAUUGUAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUACGCAG 6652
120 UACAAUGA G CCCAAGGU 570 ACCUUGGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCAUUGUA 6653
127 AGCCCAAG G UGACGACA 571 UGUCGUCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUUGGGCU 6654
137 GACGACAA G CUGCCCCC 572 GGGGGCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUGUCGUC 6655
140 GACAAGCU G CCCCCAGC 573 GCUGGGGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCUUGUC 6656
147 UGCCCCCA G CAGGGCCU 574 AGGCCCUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGGGGCA 6657
152 CCAGCAGG G CCUGCAGG 575 CCUGCAGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCUGCUGG 6658
156 CAGGGCCU G CAGGCUGU 576 ACAGCCUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGCCCUG 6659
160 GCCUGCAG G CUGUGCCC 577 GGGCACAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUGCAGGC 6660
163 UGCAGGCU G UGCCCGUG 578 CACGGGCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCCUGCA 6661
165 CAGGCUGU G CCCGUGGG 579 CCCACGGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACAGCCUG 6662
169 CUGUGCCC G UGGGCAUC 580 GAUGCCCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGGCACAG 6663
173 GCCCGUGG G CAUCCCUG 581 CAGGGAUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCACGGGC 6664
181 GCAUCCCU G CUGCCAGC 582 GCUGGCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGGAUGC 6665
184 UCCCUGCU G CCAGCCAG 583 CUGGCUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCAGGGA 6666
188 UGCUGCCA G CCAGCGCA 584 UGCGCUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGCAGCA 6667
192 GCCAGCCA G CGCAUCUU 585 AAGAUGCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGCUGGC 6668
Figure imgf000125_0001
194 CAGCCAGC G CAUCUUCC 586 GGAAGAUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCUGGCUG 6669
204 AUCUUCCU G CACGGCAA 587 UUGCCGUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGAAGAU 6670
209 CCUGCACG G CAACCGCA 588 UGCGGUUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGUGCAGG 6671
572 CCUGCACG G CAACCGCA 588 UGCGGUUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGUGCAGG 6671
215 CGGCAACC G CAUCUCGC 589 GCGAGAUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGUUGCCG 6672
222 CGCAUCUC G CAUGUGCC 590 GGCACAUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GAGAUGCG 6673
226 UCUCGCAU G UGCCAGCU 591 AGCUGGCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUGCGAGA 6674
228 UCGCAUGU G CCAGCUGC 592 GCAGCUGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACAUGCGA 6675
232 AUGUGCCA G CUGCCAGC 593 GCUGGCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGCACAU 6676
235 UGCCAGCU G CCAGCUUC 594 GAAGCUGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCUGGCA 6677
239 AGCUGCCA G CUUCCGUG 595 CACGGAAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGCAGCU 6678
245 CAGCUUCC G UGCCUGCC 596 GGCAGGCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGAAGCUG 6679
247 GCUUCCGU G CCUGCCGC 597 GCGGCAGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACGGAAGC 6680
251 CCGUGCCU G CCGCAACC 598 GGUUGCGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGCACGG 6681
254 UGCCUGCC G CAACCUCA 599 UGAGGUUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGCAGGCA 6682
270 ACCAUCCU G UGGCUGCA 600 UGCAGCCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGAUGGU 6683
273 AUCCUGUG G CUGCACUC 601 GAGUGCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CACAGGAU 6684
276 CUGUGGCU G CACUCGAA 602 UUCGAGUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCCACAG 6685
286 ACUCGAAU G UGCUGGCC 603 GGCCAGCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUUCGAGU 6686
288 UCGAAUGU G CUGGCCCG 604 CGGGCCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACAUUCGA 6687
292 AUGUGCUG G CCCGAAUU 605 AAUUCGGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGCACAU 6688
304 GAAUUGAU G CGGCUGCC 606 GGCAGCCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUCAAUUC 6689
307 UUGAUGCG G CUGCCUUC 607 GAAGGCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGCAUCAA 6690
310 AUGCGGCU G CCUUCACU 608 AGUGAAGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCCGCAU 6691
320 CUUCACUG G CCUGGCCC 609 GGGCCAGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGUGAAG 6692
325 CUGGCCUG G CCCUCCUG 610 CAGGAGGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGGCCAG 6693
336 CUCCUGGA G CAGCUGGA 611 UCCAGCUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCAGGAG 6694
339 CUGGAGCA G CUGGACCU 612 AGGUCCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGCUCCAG 6695
350 GGACCUCA G CGAUAAUG 613 CAUUAUCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGAGGUCC 6696
358 GCGAUAAU G CACAGCUC 614 GAGCUGUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUUAUCGC 6697
363 AAUGCACA G CUCCGGUC 615 GACCGGAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGUGCAUU 6698
369 CAGCUCCG G UCUGUGGA 616 UCCACAGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGGAGCUG 6699
373 UCCGGUCU G UGGACCCU 617 AGGGUCCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGACCGGA 6700
382 UGGACCCU G CCACAUUC 618 GAAUGUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGGUCCA 6701
395 AUUCCACG G CCUGGGCC 619 GGCCCAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGUGGAAU 6702
401 CGGCCUGG G CCGCCUAC 620 GUAGGCGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCAGGCCG 6703
404 CCUGGGCC G CCUACACA 621 UGUGUAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGCCCAGG 6704
Figure imgf000126_0001
414 CUACACAC G CUGCACCU 622 AGGUGCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GUGUGUAG 6705
417 CACACGCU G CACCUGGA 623 UCCAGGUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCGUGUG 6706
428 CCUGGACC G CUGCGGCC 624 GGCCGCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGUCCAGG 6707
431 GGACCGCU G CGGCCUGC 625 GCAGGCCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCGGUCC 6708
434 CCGCUGCG G CCUGCAGG 626 CCUGCAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGCAGCGG 6709
438 UGCGGCCU G CAGGAGCU 627 AGCUCCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGCCGCA 6710
444 CUGCAGGA G CUGGGCCC 628 GGGCCCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCUGCAG 6711
449 GGAGCUGG G CCCGGGGC 629 GCCCCGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCAGCUCC 6712
456 GGCCCGGG G CUGUUCCG 630 CGGAACAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCCGGGCC 6713
459 CCGGGGCU G UUCCGCGG 631 CCGCGGAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCCCCGG 6714
464 GCUGUUCC G CGGCCUGG 632 CCAGGCCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGAACAGC 6715
467 GUUCCGCG G CCUGGCUG 633 CAGCCAGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGCGGAAC 6716
472 GCGGCCUG G CUGCCCUG 634 CAGGGCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGGCCGC 6717
475 GCCUGGCU G CCCUGCAG 635 CUGCAGGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCCAGGC 6718
480 GCUGCCCU G CAGUACCU 636 AGGUACUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGGCAGC 6719
483 GCCCUGCA G UACCUCUA 637 UAGAGGUA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGCAGGGC 6720
495 CUCUACCU G CAGGACAA 638 UUGUCCUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGUAGAG 6721
505 AGGACAAC G CGCUGCAG 639 CUGCAGCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GUUGUCCU 6722
507 GACAACGC G CUGCAGGC 640 GCCUGCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCGUUGUC 6723
510 AACGCGCU G CAGGCACU 641 AGUGCCUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCGCGUU 6724
514 CGCUGCAG G CACUGCCU 642 AGGCAGUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUGCAGCG 6725
519 CAGGCACU G CCUGAUGA 643 UCAUCAGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGUGCCUG 6726
536 CACCUUCC G CGACCUGG 644 CCAGGUCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGAAGGUG 6727
545 CGACCUGG G CAACCUCA 645 UGAGGUUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCAGGUCG 6728
567 CUCUUCCU G CACGGCAA 646 UUGCCGUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGAAGAG 6729
578 CGGCAACC G CAUCUCCA 647 UGGAGAUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGUUGCCG 6730
587 CAUCUCCA G CGUGCCCG 648 CGGGCACG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGAGAUG 6731
589 UCUCCAGC G UGCCCGAG 649 CUCGGGCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCUGGAGA 6732
591 UCCAGCGU G CCCGAGCG 650 CGCUCGGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACGCUGGA 6733
597 GUGCCCGA G CGCGCCUU 651 AAGGCGCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCGGGCAC 6734
599 GCCCGAGC G CGCCUUCC 652 GGAAGGCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCUCGGGC 6735
601 CCGAGCGC G CCUUCCGU 653 ACGGAAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCGCUCGG 6736
608 CGCCUUCC G UGGGCUGC 654 GCAGCCCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGAAGGCG 6737
612 UUCCGUGG G CUGCACAG 655 CUGUGCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCACGGAA 6738
615 CGUGGGCU G CACAGCCU 656 AGGCUGUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCCCACG 6739
620 GCUGCACA G CCUCGACC 657 GGUCGAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUGCAGC 6740
629 CCUCGACC G UCUCCUAC 658 GUAGGAGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGUCGAGG 6741
Figure imgf000127_0001
639 CUCCUACU G CACCAGAA 659 UUCUGGUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGUAGGAG 6742
650 CCAGAACC G CGUGGCCC 660 GGGCCACG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGUUCUGG 6743
652 AGAACCGC G UGGCCCAU 661 AUGGGCCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCGGUUCU 6744
655 ACCGCGUG G CCCAUGUG 662 CACAUGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CACGCGGU 6745
661 UGGCCCAU G UGCACCCG 663 CGGGUGCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUGGGCCA 6746
663 GCCCAUGU G CACCCGCA 664 UGCGGGUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACAUGGGC 6747
669 GUGCACCC G CAUGCCUU 665 AAGGCAUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGGUGCAC 6748
673 ACCCGCAU G CCUUCCGU 666 ACGGAAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUGCGGGU 6749
680 UGCCUUCC G UGACCUUG 667 CAAGGUCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGAAGGCA 6750
689 UGACCUUG G CCGCCUCA 668 UGAGGCGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAAGGUCA 6751
692 CCUUGGCC G CCUCAUGA 669 UCAUGAGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGCCAAGG 6752
711 CUCUAUCU G UUUGCCAA 670 UUGGCAAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGAUAGAG 6753
715 AUCUGUUU G CCAACAAU 671 AUUGUUGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAACAGAU 6754
730 AUCUAUCA G CGCUGCCC 672 GGGCAGCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGAUAGAU 6755
732 CUAUCAGC G CUGCCCAC 673 GUGGGCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCUGAUAG 6756
735 UCAGCGCU G CCCACUGA 674 UCAGUGGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCGCUGA 6757
745 CCACUGAG G CCCUGGCC 675 GGCCAGGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUCAGUGG 6758
751 AGGCCCUG G CCCCCCUG 676 CAGGGGGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGGGCCU 6759
759 GCCCCCCU G CGUGCCCU 677 AGGGCACG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGGGGGC 6760
761 CCCCCUGC G UGCCCUGC 678 GCAGGGCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCAGGGGG 6761
763 CCCUGCGU G CCCUGCAG 679 CUGCAGGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACGCAGGG 6762
768 CGUGCCCU G CAGUACCU 680 AGGUACUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGGCACG 6763
771 GCCCUGCA G UACCUGAG 681 CUCAGGUA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGCAGGGC 6764
780 UACCUGAG G CUCAACGA 682 UCGUUGAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUCAGGUA 6765
799 ACCCCUGG G UGUGUGAC 683 GUCACACA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCAGGGGU 6766
801 CCCUGGGU G UGUGACUG 684 CAGUCACA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACCCAGGG 6767
803 CUGGGUGU G UGACUGCC 685 GGCAGUCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACACCCAG 6768
809 GUGUGACU G CCGGGCAC 686 GUGCCCGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGUCACAC 6769
814 ACUGCCGG G CACGCCCA 687 UGGGCGUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCGGCAGU 6770
818 CCGGGCAC G CCCACUCU 688 AGAGUGGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GUGCCCGG 6771
829 CACUCUGG G CCUGGCUG 689 CAGCCAGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCAGAGUG 6772
834 UGGGCCUG G CUGCAGAA 690 UUCUGCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGGCCCA 6773
837 GCCUGGCU G CAGAAGUU 691 AACUUCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCCAGGC 6774
843 CUGCAGAA G UUCCGCGG 692 CCGCGGAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCUGCAG 6775
848 GAAGUUCC G CGGCUCCU 693 AGGAGCCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGAACUUC 6776
851 GUUCCGCG G CUCCUCCU 694 AGGAGGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGCGGAAC 6777
865 CCUCCGAG G UGCCCUGC 695 GCAGGGCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCGGAGG 6778
Figure imgf000128_0001
867 UCCGAGGU G CCCUGCAG 696 CUGCAGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACCUCGGA 6779
872 GGUGCCCU G CAGCCUCC 697 GGAGGCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGGCACC 6780
875 GCCCUGCA G CCUCCCGC 698 GCGGGAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCAGGGC 6781
882 AGCCUCCC G CAACGCCU 699 AGGCGUUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGGAGGCU 6782
887 CCCGCAAC G CCUGGCUG 700 CAGCCAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GUUGCGGG 6783
892 AACGCCUG G CUGGCCGU 701 ACGGCCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGGCGUU 6784
896 CCUGGCUG G CCGUGACC 702 GGUCACGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGCCAGG 6785
899 GGCUGGCC G UGACCUCA 703 UGAGGUCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGCCAGCC 6786
911 CCUCAAAC G CCUAGCUG 704 CAGCUAGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GUUUGAGG 6787
916 AACGCCUA G CUGCCAAU 705 AUUGGCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UAGGCGUU 6788
919 GCCUAGCU G CCAAUGAC 706 GUCAUUGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCUAGGC 6789
930 AAUGACCU G CAGGGCUG 707 CAGCCCUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGUCAUU 6790
935 CCUGCAGG G CUGCGCUG 708 CAGCGCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCUGCAGG 6791
938 GCAGGGCU G CGCUGUGG 709 CCACAGCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCCCUGC 6792
940 AGGGCUGC G CUGUGGCC 710 GGCCACAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCAGCCCU 6793
943 GCUGCGCU G UGGCCACC 711 GGUGGCCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCGCAGC 6794
946 GCGCUGUG G CCACCGGC 712 GCCGGUGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CACAGCGC 6795
953 GGCCACCG G CCCUUACC 713 GGUAAGGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGGUGGCC 6796
977 CUGGACCG G CAGGGCCA 714 UGGCCCUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGGUCCAG 6797
982 CCGGCAGG G CCACCGAU 715 AUCGGUGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCUGCCGG 6798
996 GAUGAGGA G CCGCUGGG 716 CCCAGCGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCUCAUC 6799
999 GAGGAGCC G CUGGGGCU 717 AGCCCCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGCUCCUC 6800
1005 CCGCUGGG G CUUCCCAA 718 UUGGGAAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCCAGCGG 6801
1014 CUUCCCAA G UGCUGCCA 719 UGGCAGCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUGGGAAG 6802
1016 UCCCAAGU G CUGCCAGC 720 GCUGGCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACUUGGGA 6803
1019 CAAGUGCU G CCAGCCAG 721 CUGGCUGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCACUUG 6804
1023 UGCUGCCA G CCAGAUGC 722 GCAUCUGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGCAGCA 6805
1030 AGCCAGAU G CCGCUGAC 723 GUCAGCGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUCUGGCU 6806
1033 CAGAUGCC G CUGACAAG 724 CUUGUCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGCAUCUG 6807
1042 CUGACAAG G CCUCAGUA 725 UACUGAGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUUGUCAG 6808
1048 AGGCCUCA G UACUGGAG 726 CUCCAGUA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGAGGCCU 6809
1056 GUACUGGA G CCUGGAAG 727 CUUCCAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCAGUAC 6810
1069 GAAGACCA G CUUCGGCA 728 UGCCGAAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGUCUUC 6811
1075 CAGCUUCG G CAGGCAAU 729 AUUGCCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGAAGCUG 6812
1079 UUCGGCAG G CAAUGCGC 730 GCGCAUUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGCCGAA 6813
1084 CAGGCAAU G CGCUGAAG 731 CUUCAGCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUUGCCUG 6814
1086 GGCAAUGC G CUGAAGGG 732 CCCUUCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCAUUGCC 6815
Figure imgf000129_0001
1097 GAAGGGAC G CGUGCCGC 733 GCGGCACG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GUCCCUUC 6816
1099 AGGGACGC G UGCCGCCC 734 GGGCGGCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCGUCCCU 6817
1101 GGACGCGU G CCGCCCGG 735 CCGGGCGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACGCGUCC 6818
1104 CGCGUGCC G CCCGGUGA 736 UCACCGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGCACGCG 6819
1109 GCCGCCCG G UGACAGCC 737 GGCUGUCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGGGCGGC 6820
1115 CGGUGACA G CCCGCCGG 738 CCGGCGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUCACCG 6821
1119 GACAGCCC G CCGGGCAA 739 UUGCCCGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGGCUGUC 6822
1124 CCCGCCGG G CAACGGCU 740 AGCCGUUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCGGCGGG 6823
1130 GGGCAACG G CUCUGGCC 741 GGCCAGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGUUGCCC 6824
1136 CGGCUCUG G CCCACGGC 742 GCCGUGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGAGCCG 6825
1143 GGCCCACG G CACAUCAA 743 UUGAUGUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGUGGGCC 6826
1173 GGGACUCU G CCUGGCUC 744 GAGCCAGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGAGUCCC 6827
1178 UCUGCCUG G CUCUGCUG 745 CAGCAGAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGGCAGA 6828
1183 CUGGCUCU G CUGAGCCC 746 GGGCUCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGAGCCAG 6829
1188 UCUGCUGA G CCCCCGCU 747 AGCGGGGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCAGCAGA 6830
1194 GAGCCCCC G CUCACUGC 748 GCAGUGAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGGGGCUC 6831
1201 CGCUCACU G CAGUGCGG 749 CCGCACUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGUGAGCG 6832
1204 UCACUGCA G UGCGGCCC 750 GGGCCGCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGCAGUGA 6833
1206 ACUGCAGU G CGGCCCGA 751 UCGGGCCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACUGCAGU 6834
1209 GCAGUGCG G CCCGAGGG 752 CCCUCGGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGCACUGC 6835
1217 GCCCGAGG G CUCCGAGC 753 GCUCGGAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCUCGGGC 6836
1224 GGCUCCGA G CCACCAGG 754 CCUGGUGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCGGAGCC 6837
1233 CCACCAGG G UUCCCCAC 755 GUGGGGAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCUGGUGG 6838
1247 CACCUCGG G CCCUCGCC 756 GGCGAGGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCGAGGUG 6839
1253 GGGCCCUC G CCGGAGGC 757 GCCUCCGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GAGGGCCC 6840
1260 CGCCGGAG G CCAGGCUG 758 CAGCCUGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUCCGGCG 6841
1265 GAGGCCAG G CUGUUCAC 759 GUGAACAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUGGCCUC 6842
1268 GCCAGGCU G UUCACGCA 760 UGCGUGAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCCUGGC 6843
1274 CUGUUCAC G CAAGAACC 761 GGUUCUUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GUGAACAG 6844
1283 CAAGAACC G CACCCGCA 762 UGCGGGUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGUUCUUG 6845
1289 CCGCACCC G CAGCCACU 763 AGUGGCUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGGUGCGG 6846
1292 CACCCGCA G CCACUGCC 764 GGCAGUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCGGGUG 6847
1298 CAGCCACU G CCGUCUGG 765 CCAGACGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGUGGCUG 6848
1301 CCACUGCC G UCUGGGCC 766 GGCCCAGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGCAGUGG 6849
1307 CCGUCUGG G CCAGGCAG 767 CUGCCUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCAGACGG 6850
1312 UGGGCCAG G CAGGCAGC 768 GCUGCCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGGCCCA 6851
1316 CCAGGCAG G CAGCGGGG 769 CCCCGCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGCCUGG 6852
Figure imgf000130_0001
1319 GGCAGGCA G CGGGGGUG 770 CACCCCCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCCUGCC 6853
1325 CAGCGGGG G UGGCGGGA 771 UCCCGCCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCCGCUG 6854
1328 CGGGGGUG G CGGGACUG 772 CAGUCCCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CACCCCCG 6855
1337 CGGGACUG G UGACUCAG 773 CUGAGUCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGUCCCG 6856
1349 CUCAGAAG G CUCAGGUG 774 CACCUGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUCUGAG 6857
1355 AGGCUCAG G UGCCCUAC 775 GUAGGGCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGAGCCU 6858
1357 GCUCAGGU G CCCUACCC 776 GGGUAGGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACCUGAGC 6859
1367 CCUACCCA G CCUCACCU 777 AGGUGAGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGGUAGG 6860
1376 CCUCACCU G CAGCCUCA 778 UGAGGCUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGUGAGG 6861
1379 CACCUGCA G CCUCACCC 779 GGGUGAGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGCAGGUG 6862
1394 CCCCCUGG G CCUGGCGC 780 GCGCCAGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCAGGGGG 6863
1399 UGGGCCUG G CGCUGGUG 781 CACCAGCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGGCCCA 6864
1401 GGCCUGGC G CUGGUGCU 782 AGCACCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCCAGGCC 6865
1405 UGGCGCUG G UGCUGUGG 783 CCACAGCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGCGCCA 6866
1407 GCGCUGGU G CUGUGGAC 784 GUCCACAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACCAGCGC 6867
1410 CUGGUGCU G UGGACAGU 785 ACUGUCCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCACCAG 6868
1417 UGUGGACA G UGCUUGGG 786 CCCAAGCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGUCCACA 6869
1419 UGGACAGU G CUUGGGCC 787 GGCCCAAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACUGUCCA 6870
1425 GUGCUUGG G CCCUGCUG 788 CAGCAGGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCAAGCAC 6871
1430 UGGGCCCU G CUGACCCC 789 GGGGUCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGGCCCA 6872
12 ACCCCUAC G AUGAAGAG 841 CUCUUCAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GUAGGGGU 6873
15 CCUACGAU G AAGAGGGC 842 GCCCUCUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUCGUAGG 6874
18 ACGAUGAA G AGGGCGUC 843 GACGCCCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUCAUCGU 6875
20 GAUGAAGA G GGCGUCCG 844 CGGACGCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCUUCAUC 6876
21 AUGAAGAG G GCGUCCGC 845 GCGGACGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUCUUCAU 6877
31 CGUCCGCU G GAGGGAGC 8 6 GCUCCCUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCGGACG 6878
32 GUCCGCUG G AGGGAGCC 847 GGCUCCCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGCGGAC 6879
34 CCGCUGGA G GGAGCCGG 848 CCGGCUCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCAGCGG 6880
35 CGCUGGAG G GAGCCGGC 849 GCCGGCUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUCCAGCG 6881
36 GCUGGAGG G AGCCGGCU 850 AGCCGGCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCUCCAGC 6882
41 AGGGAGCC G GCUGCUGG 851 CCAGCAGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGCUCCCU 6883
CGGCUGCU G GCAUGGGU 852 ACCCAUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCAGCCG 6884
GCUGGCAU G GGUGCUGU 853 ACAGCACC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUGCCAGC 6885
CUGGCAUG G GUGCUGUG 854 CACAGCAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUGCCAG 6886
GGUGCUGU G GCUGCAGG 855 CCUGCAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACAGCACC 6887
UGGCUGCA G GCCUGGCA 856 UGCCAGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCAGCCA 6888
GCAGGCCU G GCAGGUGG 857 CCACCUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGCCUGC 6889
Figure imgf000131_0001
GCCUGGCA G GUGGCAGC 858 GCUGCCAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCCAGGC 6890
UGGCAGGU G GCAGCCCC 859 GGGGCUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACCUGCCA 6891
CAUGCCCA G GUGCCUGC 860 GCAGGCAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGGCAUG 6892
GCUACAAU G AGCCCAAG 861 CUUGGGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUUGUAGC 6893
GAGCCCAA G GUGACGAC 862 GUCGUCAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGGGCUC 6894
CCCAAGGU G ACGACAAG 863 CUUGUCGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACCUUGGG 6895
AAGGUGAC G ACAAGCUG 864 CAGCUUGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GUCACCUU 6896
CCCCAGCA G GGCCUGCA 865 UGCAGGCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGCUGGGG 6897
CCCAGCAG G GCCUGCAG 866 CUGCAGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUGCUGGG 6898
GGCCUGCA G GCUGUGCC 867 GGCACAGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGCAGGCC 6899
GUGCCCGU G GGCAUCCC 868 GGGAUGCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACGGGCAC 6900
UGCCCGUG G GCAUCCCU 869 AGGGAUGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CACGGGCA 6901
UCCUGCAC G GCAACCGC 870 GCGGUUGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GUGCAGGA 6902
UCCUGCAC G GCAACCGC 870 GCGGUUGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GUGCAGGA 6902
CAUCCUGU G GCUGCACU 871 AGUGCAGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACAGGAUG 6903
CUGCACUC G AAUGUGCU 872 AGCACAUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GAGUGCAG 6904
AAUGUGCU G GCCCGAAU 873 AUUCGGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCACAUU 6905
GCUGGCCC G AAUUGAUG 874 CAUCAAUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGGCCAGC 6906
CCCGAAUU G AUGCGGCU 875 AGCCGCAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAUUCGGG 6907
AUUGAUGC G GCUGCCUU 876 AAGGCAGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCAUCAAU 6908
CCUUCACU G GCCUGGCC 877 GGCCAGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGUGAAGG 6909
ACUGGCCU G GCCCUCCU 878 AGGAGGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGCCAGU 6910
GCCCUCCU G GAGCAGCU 879 AGCUGCUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGAGGGC 6911
CCCUCCUG G AGCAGCUG 880 CAGCUGCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGGAGGG 6912
GAGCAGCU G GACCUCAG 881 CUGAGGUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCUGCUC 6913
AGCAGCUG G ACCUCAGC 882 GCUGAGGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGCUGCU 6914
ACCUCAGC G AUAAUGCA 883 UGCAUUAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCUGAGGU 6915
ACAGCUCC G GUCUGUGG 884 CCACAGAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGAGCUGU 6916
CGGUCUGU G GACCCUGC 885 GCAGGGUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACAGACCG 6917
GGUCUGUG G ACCCUGCC 886 GGCAGGGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CACAGACC 6918
CAUUCCAC G GCCUGGGC 887 GCCCAGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GUGGAAUG 6919
399 CACGGCCU G GGCCGCCU 888 AGGCGGCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGCCGUG 6920
400 ACGGCCUG G GCCGCCUA 889 UAGGCGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGGCCGU 6921
423 CUGCACCU G GACCGCUG 890 CAGCGGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGUGCAG 6922
424 UGCACCUG G ACCGCUGC 891 GCAGCGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGGUGCA 6923
433 ACCGCUGC G GCCUGCAG 892 CUGCAGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCAGCGGU 6924
441 GGCCUGCA G GAGCUGGG 893 CCCAGCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCAGGCC 6925
Figure imgf000132_0001
442 GCCUGCAG G AGCUGGGC 894 GCCCAGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGCAGGC 6926
447 CAGGAGCU G GGCCCGGG 895 CCCGGGCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCUCCUG 6927
448 AGGAGCUG G GCCCGGGG 896 CCCCGGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGCUCCU 6928
453 CUGGGCCC G GGGCUGUU 897 AACAGCCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGGCCCAG 6929
454 UGGGCCCG G GGCUGUUC 898 GAACAGCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGGGCCCA 6930
455 GGGCCCGG G GCUGUUCC 899 GGAACAGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCGGGCCC 6931
466 UGUUCCGC G GCCUGGCU 900 AGCCAGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCGGAACA 6932
471 CGCGGCCU G GCUGCCCU 901 AGGGCAGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGCCGCG 6933
498 UACCUGCA G GACAACGC 902 GCGUUGUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGCAGGUA 6934
499 ACCUGCAG G ACAACGCG 903 CGCGUUGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUGCAGGU 6935
513 GCGCUGCA G GCACUGCC 904 GGCAGUGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGCAGCGC 6936
523 CACUGCCU G AUGACACC 905 GGUGUCAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGCAGUG 6937
526 UGCCUGAU G ACACCUUC 906 GAAGGUGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUCAGGCA 6938
538 CCUUCCGC G ACCUGGGC 907 GCCCAGGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCGGAAGG 6939
543 CGCGACCU G GGCAACCU 908 AGGUUGCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGUCGCG 6940
544 GCGACCUG G GCAACCUC 909 GAGGUUGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGGUCGC 6941
595 GCGUGCCC G AGCGCGCC 910 GGCGCGCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGGCACGC 6942
610 CCUUCCGU G GGCUGCAC 911 GUGCAGCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACGGAAGG 6943
611 CUUCCGUG G GCUGCACA 912 UGUGCAGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CACGGAAG 6944
625 ACAGCCUC G ACCGUCUC 913 GAGACGGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GAGGCUGU 6945
645 CUGCACCA G AACCGCGU 914 ACGCGGUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGUGCAG 6946
654 AACCGCGU G GCCCAUGU 915 ACAUGGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACGCGGUU 6947
682 CCUUCCGU G ACCUUGGC 916 GCCAAGGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACGGAAGG 6948
688 GUGACCUU G GCCGCCUC 917 GAGGCGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAGGUCAC 6949
699 CGCCUCAU G ACACUCUA 918 UAGAGUGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUGAGGCG 6950
7 2 UGCCCACU G AGGCCCUG 919 CAGGGCCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGUGGGCA 6951
7 CCCACUGA G GCCCUGGC 920 GCCAGGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCAGUGGG 6952
750 GAGGCCCU G GCCCCCCU 921 AGGGGGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGGCCUC 6953
777 CAGUACCU G AGGCUCAA 922 UUGAGCCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGUACUG 6954
779 GUACCUGA G GCUCAACG 923 CGUUGAGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCAGGUAC 6955
787 GGCUCAAC G ACAACCCC 924 GGGGUUGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GUUGAGCC 6956
797 CAACCCCU G GGUGUGUG 925 CACACACC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGGGUUG 6957
798 AACCCCUG G GUGUGUGA 926 UCACACAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGGGGUU 6958
805 GGGUGUGU G ACUGCCGG 927 CCGGCAGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACACACCC 6959
812 UGACUGCC G GGCACGCC 928 GGCGUGCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGCAGUCA 6960
813 GACUGCCG G GCACGCCC 929 GGGCGUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGGCAGUC 6961
827 CCCACUCU G GGCCUGGC 930 GCCAGGCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAGUGGG 6962
Figure imgf000133_0001
828 CCACUCUG G GCCUGGCU 931 AGCCAGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGAGUGG 6963
833 CUGGGCCU G GCUGGAGA 932 UCUGCAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGCCCAG 6964
840 UGGCUGCA G AAGUUCCG 933 CGGAACUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCAGCCA 6965
850 AGUUCCGC G GCUCCUCC 934 GGAGGAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCGGAACU 6966
862 CCUCCUCC G AGGUGCCC 935 GGGCACCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGAGGAGG 6967
864 UCCUCCGA G GUGCCCUG 936 CAGGGCAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCGGAGGA 6968
891 CAACGCCU G GCUGGCCG 937 CGGCCAGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGCGUUG 6969
895 GCCUGGCU G GCCGUGAC 938 GUCACGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCCAGGC 6970
901 CUGGCCGU G ACCUCAAA 939 UUUGAGGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACGGCCAG 6971
925 CUGCCAAU G ACCUGCAG 940 CUGCAGGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUUGGCAG 6972
933 GACCUGCA G GGCUGCGC 941 GCGCAGCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGCAGGUC 6973
934 ACCUGCAG G GCUGCGCU 942 AGCGCAGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUGCAGGU 6974
945 UGCGCUGU G GCCACCGG 943 CCGGUGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACAGCGCA 6975
952 UGGCCACC G GCCCUUAC 944 GUAAGGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGUGGCCA 6976
971 UCCCAUCU G GACCGGCA 945 UGCCGGUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGAUGGGA 6977
972 CCCAUCUG G ACCGGCAG 946 CUGCCGGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGAUGGG 6978
976 UCUGGACC G GCAGGGCC 947 GGCCCUGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGUCCAGA 6979
980 GACCGGCA G GGCCACCG 948 CGGUGGCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGCCGGUC 6980
981 ACCGGCAG G GCCACCGA 949 UCGGUGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUGCCGGU 6981
988 GGGCCACC G AUGAGGAG 950 CUCCUCAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGUGGCCC 6982
991 CCACCGAU G AGGAGCCG 951 CGGCUCCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUCGGUGG 6983
993 ACCGAUGA G GAGCCGCU 952 AGCGGCUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCAUCGGU 6984
994 CCGAUGAG G AGCCGCUG 953 CAGCGGCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUCAUCGG 6985
1002 GAGCCGCU G GGGCUUCC 954 GGAAGCCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCGGCUC 6986
1003 AGCCGCUG G GGCUUCCC 955 GGGAAGCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGCGGCU 6987
1004 GCCGCUGG G GCUUCCCA 956 UGGGAAGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCAGCGGC 6988
1027 GCCAGCCA G AUGCCGCU 957 AGCGGCAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGCUGGC 6989
1036 AUGCCGCU G ACAAGGCC 958 GGCCUUGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCGGCAU 6990
1041 GCUGACAA G GCCUCAGU 959 ACUGAGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUGUCAGC 6991
1053 UCAGUACU G GAGCCUGG 960 CCAGGCUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGUACUGA 6992
1054 CAGUACUG G AGCCUGGA 961 UCCAGGCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGUACUG 6993
1060 UGGAGCCU G GAAGACCA 962 UGGUCUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGCUCCA 6994
1061 GGAGCCUG G AAGACCAG 963 CUGGUCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGGCUCC 6995
1064 GCCUGGAA G ACCAGCUU 964 AAGCUGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCCAGGC 6996
1074 CCAGCUUC G GCAGGCAA 965 UUGCCUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GAAGCUGG 6997
1078 CUUCGGCA G GCAAUGCG 966 CGCAUUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCCGAAG 6998
1089 AAUGCGCU G AAGGGACG 967 CGUCCCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCGCAUU 6999
Figure imgf000134_0001
1092 GCGCUGAA G GGACGCGU 968 ACGCGUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCAGCGC 7000
1093 CGCUGAAG G GACGCGUG 969 CACGCGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUCAGCG 7001
1094 GCUGAAGG G ACGCGUGC 970 GCACGCGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCUUCAGC 7002
1108 UGCCGCCC G GUGACAGC 971 GCUGUCAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGGCGGCA 7003 llll CGCCCGGU G ACAGCCCG 972 CGGGCUGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACCGGGCG 7004
1122 AGCCCGCC G GGCAACGG 973 CCGUUGCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGCGGGCU 7005
1123 GCCCGCCG G GCAACGGC 974 GCCGUUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGGCGGGC 7006
1129 CGGGCAAC G GCUCUGGC 975 GCCAGAGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GUUGCCCG 7007
1135 ACGGCUCU G GCCCACGG 976 CCGUGGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGAGCCGU 7008
1142 UGGCCCAC G GCACAUCA 977 UGAUGUGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GUGGGCCA 7009
1153 ACAUCAAU G ACUCACCC 978 GGGUGAGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUUGAUGU 7010
1165 CACCCUUU G GGACUCUG 979 CAGAGUCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAAGGGUG 7011
1166 ACCCUUUG G GACUCUGC 980 GCAGAGUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAAAGGGU 7012
1167 CCCUUUGG G ACUCUGCC 981 GGCAGAGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCAAAGGG 7013
1177 CUCUGCCU G GCUCUGCU 982 AGCAGAGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGCAGAG 7014
1186 GCUCUGCU G AGCCCCCG 983 CGGGGGCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCAGAGC 7015
1208 UGCAGUGC G GCCCGAGG 984 CCUCGGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCACUGCA 7016
1213 UGCGGCCC G AGGGCUCC 985 GGAGCCCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGGCCGCA 7017
1215 CGGCCCGA G GGCUCCGA 986 UCGGAGCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCGGGCCG 7018
1216 GGCCCGAG G GCUCCGAG 987 CUCGGAGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUCGGGCC 7019
1222 AGGGCUCC G AGCCACCA 988 UGGUGGCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGAGCCCU 7020
1231 AGCCACCA G GGUUCCCC 989 GGGGAACC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGUGGCU 7021
1232 GCCACCAG G GUUCCCCA 990 UGGGGAAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUGGUGGC 7022
1245 CCCACCUC G GGCCCUCG 991 CGAGGGCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GAGGUGGG 7023
1246 CCACCUCG G GCCCUCGC 992 GCGAGGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGAGGUGG 7024
1256 CCCUCGCC G GAGGCCAG 993 CUGGCCUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGCGAGGG 7025
1257 CCUCGCCG G AGGCCAGG 994 CCUGGCCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGGCGAGG 7026
1259 UCGCCGGA G GCCAGGCU 995 AGCCUGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCGGCGA 7027
1264 GGAGGCCA G GCUGUUCA 996 UGAACAGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGCCUCC 7028
1278 UCACGCAA G AACCGCAC 997 GUGCGGUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUGCGUGA 7029
1305 UGCCGUCU G GGCCAGGC 998 GCCUGGCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGACGGCA 7030
1306 GCCGUCUG G GCCAGGCA 999 UGCCUGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGACGGC 7031
1311 CUGGGCCA G GCAGGCAG 1000 CUGCCUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGCCCAG 7032
1315 GCCAGGCA G GCAGCGGG 1001 CCCGCUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCCUGGC 7033
1321 CAGGCAGC G GGGGUGGC 1002 GCCACCCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCUGCCUG 7034
1322 AGGCAGCG G GGGUGGCG 1003 CGCCACCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGCUGCCU 7035
1323 GGCAGCGG G GGUGGCGG 1004 CCGCCACC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCGCUGCC 7036
Figure imgf000135_0001
1324 GCAGCGGG G GUGGCGGG 1005 CCCGCCAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCGCUGC 7037
1327 GCGGGGGU G GCGGGACU 1006 AGUCCCGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACCCCCGC 7038
1330 GGGGUGGC G GGACUGGU 1007 ACCAGUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCCACCCC 7039
1331 GGGUGGCG G GACUGGUG 1008 CACCAGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGCCACCC 7040
1332 GGUGGCGG G ACUGGUGA 1009 UCACCAGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCGCCACC 7041
1336 GCGGGACU G GUGACUCA 1010 UGAGUCAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGUCCCGC 7042
1339 GGACUGGU G ACUCAGAA 1011 UUCUGAGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACCAGUCC 7043
1345 GUGACUCA G AAGGCUCA 1012 UGAGCCUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGAGUCAC 7044
1348 ACUCAGAA G GCUCAGGU 1013 ACCUGAGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUCUGAGU 7045
1354 AAGGCUCA G GUGCCCUA 1014 UAGGGCAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGAGCCUU 7046
1392 ACCCCCCU G GGCCUGGC 1015 GCCAGGCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGGGGGU 7047
1393 CCCCCCUG G GCCUGGCG 1016 CGCCAGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGGGGGG 7048
1398 CUGGGCCU G GCGCUGGU 1017 ACCAGCGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGCCCAG 7049
1404 CUGGCGCU G GUGCUGUG 1018 CACAGCAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCGCCAG 7050
1412 GGUGCUGU G GACAGUGC 1019 GCACUGUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACAGCACC 7051
1413 GUGCUGUG G ACAGUGCU 1020 AGCACUGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CACAGCAC 7052
1423 CAGUGCUU G GGCCCUGC 1021 GCAGGGCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAGCACUG 7053
1424 AGUGCUUG G GCCCUGCU 1022 AGCAGGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAAGCACU 7054
1433 GCCCUGCU G ACCCCCAG 1023 CUGGGGGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCAGGGC 7055
Input Sequence = AF283463. Cut Site = GI.
Arm Length = 8. Core Sequence = GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG
AF283463 (Homo sapiens Nogo receptor mRNA, complete cds.; 1441 bp)
Table VIII: Human IKK-gamma Hammerhead and Substrate Sequence
Pos Substrate Seq Hammerhead Seq ID ID
18 AUGGCCCU U GUGAUCCA 1024 UGGAUCAC CUGAUGAGGCCGUUAGGCCGAA AGGGCCAU 7056
24 CUUGUGAU C CAGGUGGG 1025 CCCACCUG CUGAUGAGGCCGUUAGGCCGAA AUCACAAG 7057
39 GGGAAACU A AGGCCCAG 1026 CUGGGCCU CUGAUGAGGCCGUUAGGCCGAA AGUUUCCC 7058
70 CGCAGACU A UCAAUCCC 1027 GGGAUUGA CUGAUGAGGCCGUUAGGCCGAA AGUCUGCG 7059
72 CAGACUAU C AAUCCCAG 1028 CUGGGAUU CUGAUGAGGCCGUUAGGCCGAA AUAGUCUG 7060
76 CUAUCAAU C CCAGUCUC 1029 GAGACUGG CUGAUGAGGCCGUUAGGCCGAA AUUGAUAG 7061
82 AUCCCAGU C UCUUCCCC 1030 GGGGAAGA CUGAUGAGGCCGUUAGGCCGAA ACUGGGAU 7062
84 CCCAGUCU C UUCCCCUC 1031 GAGGGGAA CUGAUGAGGCCGUUAGGCCGAA AGACUGGG 7063
86 CAGUCUCU U CCCCUCAC 1032 GUGAGGGG CUGAUGAGGCCGUUAGGCCGAA AGAGACUG 7064
87 AGUCUCUU C CCCUCACU 1033 AGUGAGGG CUGAUGAGGCCGUUAGGCCGAA AAGAGACU 7065
92 CUUCCCCU C ACUCCCUG 1034 CAGGGAGU CUGAUGAGGCCGUUAGGCCGAA AGGGGAAG 7066
96 CCCUCACU C CCUGUGAA 1035 UUCACAGG CUGAUGAGGCCGUUAGGCCGAA AGUGAGGG 7067
108 GUGAAGCU C UCCAGCAU 1036 AUGCUGGA CUGAUGAGGCCGUUAGGCCGAA AGCUUCAC 7068
110 GAAGCUCU C CAGCAUCA 1037 UGAUGCUG CUGAUGAGGCCGUUAGGCCGAA AGAGCUUC 7069
117 UCCAGCAU C AUCGAGGU 1038 ACCUCGAU CUGAUGAGGCCGUUAGGCCGAA AUGCUGGA 7070
120 AGCAUCAU C GAGGUCCC 1039 GGGACCUC CUGAUGAGGCCGUUAGGCCGAA AUGAUGCU 7071
126 AUCGAGGU c CCAUCAGC 1040 GCUGAUGG CUGAUGAGGCCGUUAGGCCGAA ACCUCGAU 7072
131 GGUCCCAU c AGCCCUUG 1041 CAAGGGCU CUGAUGAGGCCGUUAGGCCGAA AUGGGACC 7073
138 UCAGCCCU u GCCCUGUU 1042 AACAGGGC CUGAUGAGGCCGUUAGGCCGAA AGGGCUGA 7074
146 UGCCCUGU u GGAUGAAU 1043 AUUCAUCC CUGAUGAGGCCGUUAGGCCGAA ACAGGGCA 7075
155 GGAUGAAU A GGCACCUC 1044 GAGGUGCC CUGAUGAGGCCGUUAGGCCGAA AUUCAUCC 7076
163 AGGCACCU c UGGAAGAG 1045 CUCUUCCA CUGAUGAGGCCGUUAGGCCGAA AGGUGCCU 7077
218 CAGCAGAU c AGGACGUA 1046 UACGUCCU CUGAUGAGGCCGUUAGGCCGAA AUCUGCUG 7078
226 CAGGACGU A CUGGGCGA 1047 UCGCCCAG CUGAUGAGGCCGUUAGGCCGAA ACGUCCUG 7079
240 CGAAGAGU c UCCUCUGG 1048 CCAGAGGA CUGAUGAGGCCGUUAGGCCGAA ACUCUUCG 7080
242 AAGAGUCU c CUCUGGGG 1049 CCCCAGAG CUGAUGAGGCCGUUAGGCCGAA AGACUCUU 7081
245 AGUCUCCU c UGGGGAAG 1050 CUUCCCCA CUGAUGAGGCCGUUAGGCCGAA AGGAGACU 7082
275 ACCUGCCU u CAGAACAG 1051 CUGUUCUG CUGAUGAGGCCGUUAGGCCGAA AGGCAGGU 7083
276 CCUGCCUU c AGAACAGG 1052 CCUGUUCU CUGAUGAGGCCGUUAGGCCGAA AAGGCAGG 7084
290 AGGGCGCU c CUGAGACC 1053 GGUCUCAG CUGAUGAGGCCGUUAGGCCGAA AGCGCCCU 7085
301 GAGACCCU c CAGCGCUG 1054 CAGCGCUG CUGAUGAGGCCGUUAGGCCGAA AGGGUCUC 7086
323 AGGAGAAU c AAGAGCUC 1055 GAGCUCUU CUGAUGAGGCCGUUAGGCCGAA AUUCUCCU 7087
331 CAAGAGCU c CGAGAUGC 1056 GCAUCUCG CUGAUGAGGCCGUUAGGCCGAA AGCUCUUG 7088
343 GAUGCCAU c CGGCAGAG 1057 CUCUGCCG CUGAUGAGGCCGUUAGGCCGAA AUGGCAUC 7089
361 AACCAGAU u CUGCGGGA 1058 UCCCGCAG CUGAUGAGGCCGUUAGGCCGAA AUCUGGUU 7090
362 ACCAGAUU c UGCGGGAG 1059 CUCCCGCA CUGAUGAGGCCGUUAGGCCGAA AAUCUGGU 7091
385 GAGGAGCU u CUGCAUUU 1060 AAAUGCAG CUGAUGAGGCCGUUAGGCCGAA AGCUCCUC 7092
386 AGGAGCUU c UGCAUUUC 1061 GAAAUGCA CUGAUGAGGCCGUUAGGCCGAA AAGCUCCU 7093
392 UUCUGCAU u UCCAAGCC 1062 GGCUUGGA CUGAUGAGGCCGUUAGGCCGAA AUGCAGAA 7094
393 UCUGCAUU u CCAAGCCA 1063 UGGCUUGG CUGAUGAGGCCGUUAGGCCGAA AAUGCAGA 7095
394 CUGCAUUU c CAAGCCAG 1064 CUGGCUUG CUGAUGAGGCCGUUAGGCCGAA AAAUGCAG 7096
423 GAAGGAGU u CCUCAUGU 1065 ACAUGAGG CUGAUGAGGCCGUUAGGCCGAA ACUCCUUC 7097
424 AAGGAGUU c CUCAUGUG 1066 CACAUGAG CUGAUGAGGCCGUUAGGCCGAA AACUCCUU 7098
427 GAGUUCCU c AUGUGCAA 1067 UUGCACAU CUGAUGAGGCCGUUAGGCCGAA AGGAACUC 7099
438 GUGCAAGU u CCAGGAGG 1068 CCUCCUGG CUGAUGAGGCCGUUAGGCCGAA ACUUGCAC 7100
439 UGCAAGUU c CAGGAGGC 1069 GCCUCCUG CUGAUGAGGCCGUUAGGCCGAA AACUUGCA 7101
469 GAGAGACU c GGCCUGGA 1070 UCCAGGCC CUGAUGAGGCCGUUAGGCCGAA AGUCUCUC 7102 484 GAGAAGCU C GAUCUGAA 1071 UUCAGAUC CUGAUGAGGCCGUUAGGCCGAA AGCUUCUC 7103
488 AGCUCGAU C UGAAGAGG 1072 CCUCUUCA CUGAUGAGGCCGUUAGGCCGAA AUCGAGCU 710
512 AGCAGGCU C UGCGGGAG 1073 CUCCCGCA CUGAUGAGGCCGUUAGGCCGAA AGCCUGCU 7105
570 CAAGGCCU C UGUGAAAG 1074 CUUUCACA CUGAUGAGGCCGUUAGGCCGAA AGGCCUUG 7106
591 GGUGACGU C CUUGCUCG 1075 CGAGCAAG CUGAUGAGGCCGUUAGGCCGAA ACGUCACC 7107
594 GACGUCCU U GCUCGGGG 1076 CCCCGAGC CUGAUGAGGCCGUUAGGCCGAA AGGACGUC 7108
598 UCCUUGCU c GGGGAGCU 1077 AGCUCCCC CUGAUGAGGCCGUUAGGCCGAA AGCAAGGA 7109
623 GCCAGAGU c GCUUGGAG 1078 CUCCAAGC CUGAUGAGGCCGUUAGGCCGAA ACUCUGGC 7110
627 GAGUCGCU u GGAGGCUG 1079 CAGCCUCC CUGAUGAGGCCGUUAGGCCGAA AGCGACUC 7111
641 CUGCCACU A AGGAAUGC 1080 GCAUUCCU CUGAUGAGGCCGUUAGGCCGAA AGUGGCAG 7112
656 GCCAGGCU C UGGAGGGU 1081 ACCCUCCA CUGAUGAGGCCGUUAGGCCGAA AGCCUGGC 7113
665 UGGAGGGU C GGGCCCGG 1082 CCGGGCCC CUGAUGAGGCCGUUAGGCCGAA ACCCUCCA 7114
787 GCCGCGCU C CGCAUGGA 1083 UCCAUGCG CUGAUGAGGCCGUUAGGCCGAA AGCGCGGC 7115
810 GGCCGCCU C GGAGGAGA 1084 UCUCCUCC CUGAUGAGGCCGUUAGGCCGAA AGGCGGCC 7116
837 GGCCCAGU U GCAGGUGG 1085 CCACCUGC CUGAUGAGGCCGUUAGGCCGAA ACUGGGCC 7117
849 GGUGGCCU A UCACCAGC 1086 GCUGGUGA CUGAUGAGGCCGUUAGGCCGAA AGGCCACC 7118
851 UGGCCUAU C ACCAGCUC 1087 GAGCUGGU CUGAUGAGGCCGUUAGGCCGAA AUAGGCCA 7119
859 CACCAGCU C UUCCAAGA 1088 UCUUGGAA CUGAUGAGGCCGUUAGGCCGAA AGCUGGUG 7120
861 CCAGCUCU U CCAAGAAU 1089 AUUCUUGG CUGAUGAGGCCGUUAGGCCGAA AGAGCUGG 7121
862 CAGCUCUU C CAAGAAUA 1090 UAUUCUUG CUGAUGAGGCCGUUAGGCCGAA AAGAGCUG 7122
870 CCAAGAAU A CGACAACC 1091 GGUUGUCG CUGAUGAGGCCGUUAGGCCGAA AUUCUUGG 7123
883 AACCACAU C AAGAGCAG 1092 CUGCUCUU CUGAUGAGGCCGUUAGGCCGAA AUGUGGUU 7124
935 UGGAAGAU C UCAAACAG 1093 CUGUUUGA CUGAUGAGGCCGUUAGGCCGAA AUCUUCCA 7125
937 GAAGAUCU C AAACAGCA 1094 UGCUGUUU CUGAUGAGGCCGUUAGGCCGAA AGAUCUUC 7126
949 CAGCAGCU C CAGCAGGC 1095 GCCUGCUG CUGAUGAGGCCGUUAGGCCGAA AGCUGCUG 7127
991 GAGGUGAU C GAUAAGCU 1096 AGCUUAUC CUGAUGAGGCCGUUAGGCCGAA AUCACCUC 7128
995 UGAUCGAU A AGCUGAAG 1097 CUUCAGCU CUGAUGAGGCCGUUAGGCCGAA AUCGAUCA 7129
1027 CACAAGAU U GUGAUGGA 1098 UCCAUCAC CUGAUGAGGCCGUUAGGCCGAA AUCUUGUG 7130
1042 GAGACCGU U CCGGUGCU 1099 AGCACCGG CUGAUGAGGCCGUUAGGCCGAA ACGGUCUC 7131
1043 AGACCGUU C CGGUGCUG 1100 CAGCACCG CUGAUGAGGCCGUUAGGCCGAA AACGGUCU 7132
1067 AGGCGGAU A UCUACAAG 1101 CUUGUAGA CUGAUGAGGCCGUUAGGCCGAA AUCCGCCU 7133
1069 GCGGAUAU C UACAAGGC 1102 GCCUUGUA CUGAUGAGGCCGUUAGGCCGAA AUAUCCGC 7134
1071 GGAUAUCU A CAAGGCGG 1103 CCGCCUUG CUGAUGAGGCCGUUAGGCCGAA AGAUAUCC 7135
1083 GGCGGACU U CCAGGCUG 1104 CAGCCUGG CUGAUGAGGCCGUUAGGCCGAA AGUCCGCC 7136
1084 GCGGACUU C CAGGCUGA 1105 UCAGCCUG CUGAUGAGGCCGUUAGGCCGAA AAGUCCGC 7137
1132 AAGGAGCU C CUGCAGGA 1106 UCCUGCAG CUGAUGAGGCCGUUAGGCCGAA AGCUCCUU 7138
1167 GAGGGAGU A CAGCAAAC 1107 GUUUGCUG CUGAUGAGGCCGUUAGGCCGAA ACUCCCUC 7139
1190 CCAGCUGU C AGGAGUCG 1108 CGACUCCU CUGAUGAGGCCGUUAGGCCGAA ACAGCUGG 7140
1197 UCAGGAGU C GGCCAGGA 1109 UCCUGGCC CUGAUGAGGCCGUUAGGCCGAA ACUCCUGA 7141
1207 GCCAGGAU C GAGGACAU 1110 AUGUCCUC CUGAUGAGGCCGUUAGGCCGAA AUCCUGGC 7142
1231 CGGCAUGU C GAGGUCUC llll GAGACCUC CUGAUGAGGCCGUUAGGCCGAA ACAUGCCG 7143
1237 GUCGAGGU C UCCCAGGC 1112 GCCUGGGA CUGAUGAGGCCGUUAGGCCGAA ACCUCGAC 7144
1239 CGAGGUCU C CCAGGCCC 1113 GGGCCUGG CUGAUGAGGCCGUUAGGCCGAA AGACCUCG 7145
1251 GGCCCCCU U GCCCCCCG 1114 CGGGGGGC CUGAUGAGGCCGUUAGGCCGAA AGGGGGCC 7146
1269 CCCUGCCU A CCUCUCCU 1115 AGGAGAGG CUGAUGAGGCCGUUAGGCCGAA AGGCAGGG 7147
1273 GCCUACCU C UCCUCUCC 1116 GGAGAGGA CUGAUGAGGCCGUUAGGCCGAA AGGUAGGC 7148
1275 CUACCUCU C CUCUCCCC 1117 GGGGAGAG CUGAUGAGGCCGUUAGGCCGAA AGAGGUAG 7149
1278 CCUCUCCU C UCCCCUGG 1118 CCAGGGGA CUGAUGAGGCCGUUAGGCCGAA AGGAGAGG 7150
1280 ucuccucu C CCCUGGCC 1119 GGCCAGGG CUGAUGAGGCCGUUAGGCCGAA AGAGGAGA 7151
1332 ACCUGACU U CUGCUGUC 1120 GACAGCAG CUGAUGAGGCCGUUAGGCCGAA AGUCAGGU 7152
1333 CCUGACUU C UGCUGUCC 1121 GGACAGCA CUGAUGAGGCCGUUAGGCCGAA AAGUCAGG 7153 1340 UCUGCUGU C CCAAGUGC 1122 GCACUUGG CUGAUGAGGCCGUUAGGCCGAA ACAGCAGA 7154
1353 GUGCCAGU A UCAGGCCC 1123 GGGCCUGA CUGAUGAGGCCGUUAGGCCGAA ACUGGCAC 7155
1355 GCCAGUAU C AGGCCCCU 1124 AGGGGCCU CUGAUGAGGCCGUUAGGCCGAA AUACUGGC 7156
1367 CCCCUGAU A UGGACACC 1125 GGUGUCCA CUGAUGAGGCCGUUAGGCCGAA AUCAGGGG 7157
1384 CUGCAGAU A CAUGUCAU 1126 AUGACAUG CUGAUGAGGCCGUUAGGCCGAA AUCUGCAG 7158
1390 AUACAUGU C AUGGAGUG 1127 CACUCCAU CUGAUGAGGCCGUUAGGCCGAA ACAUGUAU 7159
1402 GAGUGCAU U GAGUAGGG 1128 CCCUACUC CUGAUGAGGCCGUUAGGCCGAA AUGCACUC 7160
1407 CAUUGAGU A GGGCCGGC 1129 GCCGGCCC CUGAUGAGGCCGUUAGGCCGAA ACUCAAUG 7161
1464 CGUGCAGU C UGCGCUUU 1130 AAAGCGCA CUGAUGAGGCCGUUAGGCCGAA ACUGCACG 7162
1471 UCUGCGCU U UCCUCUCC 1131 GGAGAGGA CUGAUGAGGCCGUUAGGCCGAA AGCGCAGA 7163
1472 CUGCGCUU U CCUCUCCC 1132 GGGAGAGG CUGAUGAGGCCGUUAGGCCGAA AAGCGCAG 7164
1473 UGCGCUUU C CUCUCCCG 1133 CGGGAGAG CUGAUGAGGCCGUUAGGCCGAA AAAGCGCA 7165
1476 GCUUUCCU C UCCCGCCU 1134 AGGCGGGA CUGAUGAGGCCGUUAGGCCGAA AGGAAAGC 7166
1478 UUUCCUCU C CCGCCUGC 1135 GCAGGCGG CUGAUGAGGCCGUUAGGCCGAA AGAGGAAA 7167
1489 GCCUGCCU A GCCCAGGA 1136 UCCUGGGC CUGAUGAGGCCGUUAGGCCGAA AGGCAGGC 7168
1565 CGGCACCU U ACGCUUCA 1137 UGAAGCGU CUGAUGAGGCCGUUAGGCCGAA AGGUGCCG 7169
1566 GGCACCUU A CGCUUCAG 1138 CUGAAGCG CUGAUGAGGCCGUUAGGCCGAA AAGGUGCC 7170
1571 CUUACGCU U CAGCUGUU 1139 AACAGCUG CUGAUGAGGCCGUUAGGCCGAA AGCGUAAG 7171
1572 UUACGCUU C AGCUGUUG 1140 CAACAGCU CUGAUGAGGCCGUUAGGCCGAA AAGCGUAA 7172
1579 UCAGCUGU U GAUCCGCU 1141 AGCGGAUC CUGAUGAGGCCGUUAGGCCGAA ACAGCUGA 7173
1583 CUGUUGAU C CGCUGGUC 1142 GACCAGCG CUGAUGAGGCCGUUAGGCCGAA AUCAACAG 7174
1591 CCGCUGGU C CCCUCUUU 1143 AAAGAGGG CUGAUGAGGCCGUUAGGCCGAA ACCAGCGG 7175
1596 GGUCCCCU C UUUUGGGG 1144 CCCCAAAA CUGAUGAGGCCGUUAGGCCGAA AGGGGACC 7176
1598 UCCCCUCU U UUGGGGUA 1145 UACCCCAA CUGAUGAGGCCGUUAGGCCGAA AGAGGGGA 7177
1599 CCCCUCUU U UGGGGUAG 1146 CUACCCCA CUGAUGAGGCCGUUAGGCCGAA AAGAGGGG 7178
1600 cccucuuu U GGGGUAGA 1147 UCUACCCC CUGAUGAGGCCGUUAGGCCGAA AAAGAGGG 7179
1606 UUUGGGGU A GAUGCGGC 1148 GCCGCAUC CUGAUGAGGCCGUUAGGCCGAA ACCCCAAA 7180
1621 GCCCCGAU C AGGCCUGA 1149 UCAGGCCU CUGAUGAGGCCGUUAGGCCGAA AUCGGGGC 7181
1632 GCCUGACU C GCUGCUCU 1150 AGAGCAGC CUGAUGAGGCCGUUAGGCCGAA AGUCAGGC 7182
1639 UCGCUGCU C UUUUUGUU 1151 AACAAAAA CUGAUGAGGCCGUUAGGCCGAA AGCAGCGA 7183
1641 GCUGCUCU U UUUGUUCC 1152 GGAACAAA CUGAUGAGGCCGUUAGGCCGAA AGAGCAGC 7184
1642 CUGCUCUU U UUGUUCCC 1153 GGGAACAA CUGAUGAGGCCGUUAGGCCGAA AAGAGCAG 7185
1643 UGCUCUUU U UGUUCCCU 1154 AGGGAACA CUGAUGAGGCCGUUAGGCCGAA AAAGAGCA 7186
1644 GCUCUUUU u GUUCCCUU 1155 AAGGGAAC CUGAUGAGGCCGUUAGGCCGAA AAAAGAGC 7187
1647 CUUUUUGU u CCCUUCUG 1156 CAGAAGGG CUGAUGAGGCCGUUAGGCCGAA ACAAAAAG 7188
1648 UUUUUGUU c CCUUCUGU 1157 ACAGAAGG CUGAUGAGGCCGUUAGGCCGAA AACAAAAA 7189
1652 UGUUCCCU u CUGUCUGC 1158 GCAGACAG CUGAUGAGGCCGUUAGGCCGAA AGGGAACA 7190
1653 GUUCCCUU c UGUCUGCU 1159 AGCAGACA CUGAUGAGGCCGUUAGGCCGAA AAGGGAAC 7191
1657 CCUUCUGU c UGCUCGAA 1160 UUCGAGCA CUGAUGAGGCCGUUAGGCCGAA ACAGAAGG 7192
1662 UGUCUGCU c GAACCACU 1161 AGUGGUUC CUGAUGAGGCCGUUAGGCCGAA AGCAGACA 7193
1671 GAACCACU u GCCUCGGG 1162 CCCGAGGC CUGAUGAGGCCGUUAGGCCGAA AGUGGUUC 7194
1676 ACUUGCCU c GGGCUAAU 1163 AUUAGCCC CUGAUGAGGCCGUUAGGCCGAA AGGCAAGU 7195
1682 CUCGGGCU A AUCCCUCC 1164 GGAGGGAU CUGAUGAGGCCGUUAGGCCGAA AGCCCGAG 7196
1685 GGGCUAAU c CCUCCCUC 1165 GAGGGAGG CUGAUGAGGCCGUUAGGCCGAA AUUAGCCC 7197
1689 UAAUCCCU c CCUCUUCC 1166 GGAAGAGG CUGAUGAGGCCGUUAGGCCGAA AGGGAUUA 7198
1693 CCCUCCCU c UUCCUCCA 1167 UGGAGGAA CUGAUGAGGCCGUUAGGCCGAA AGGGAGGG 7199
1695 CUCCCUCU u CCUCCACC 1168 GGUGGAGG CUGAUGAGGCCGUUAGGCCGAA AGAGGGAG 7200
1696 ucccucuu c CUCCACCC 1169 GGGUGGAG CUGAUGAGGCCGUUAGGCCGAA AAGAGGGA 7201
1699 cucuuccu c CACCCGGC 1170 GCCGGGUG CUGAUGAGGCCGUUAGGCCGAA AGGAAGAG 7202
1719 GGGGAAGU c AAGAAUGG 1171 CCAUUCUU CUGAUGAGGCCGUUAGGCCGAA ACUUCCCC 7203
1739 CUGGGGCU c UCAGGGAG 1172 CUCCCUGA CUGAUGAGGCCGUUAGGCCGAA AGCCCCAG 7204 1741 GGGGCUCU C AGGGAGAA 1173 UUCUCCCU CUGAUGAGGCCGUUAGGCCGAA AGAGCCCC 7205
1755 GAACUGCU U CCCCUGGC 1174 GCCAGGGG CUGAUGAGGCCGUUAGGCCGAA AGCAGUUC 7206
1756 AACUGCUU C CCCUGGCA 1175 UGCCAGGG CUGAUGAGGCCGUUAGGCCGAA AAGCAGUU 7207
1781 UGGCAGCU C UUCCUCCC 1176 GGGAGGAA CUGAUGAGGCCGUUAGGCCGAA AGCUGCCA 7208
1783 GCAGCUCU U CCUCCCAC 1177 GUGGGAGG CUGAUGAGGCCGUUAGGCCGAA AGAGCUGC 7209
1784 CAGCUCUU C CUCCCACC 1178 GGUGGGAG CUGAUGAGGCCGUUAGGCCGAA AAGAGCUG 7210
1787 CUCUUCCU C CCACCGGA 1179 UCCGGUGG CUGAUGAGGCCGUUAGGCCGAA AGGAAGAG 7211
1836 GCUGCCCU C UUACCAUG 1180 CAUGGUAA CUGAUGAGGCCGUUAGGCCGAA AGGGCAGC 7212
1838 UGCCCUCU U ACCAUGCA 1181 UGCAUGGU CUGAUGAGGCCGUUAGGCCGAA AGAGGGCA 7213
1839 GCCCUCUU A CCAUGCAC 1182 GUGCAUGG CUGAUGAGGCCGUUAGGCCGAA AAGAGGGC 7214
1857 CGGGUGCU C UCCUUUUG 1183 CAAAAGGA CUGAUGAGGCCGUUAGGCCGAA AGCACCCG 7215
1859 GGUGCUCU C CUUUUGGG 1184 CCCAAAAG CUGAUGAGGCCGUUAGGCCGAA AGAGCACC 7216
1862 GCUCUCCU U UUGGGCUG 1185 CAGCCCAA CUGAUGAGGCCGUUAGGCCGAA AGGAGAGC 7217
1863 CUCUCCUU u UGGGCUGC 1186 GCAGCCCA CUGAUGAGGCCGUUAGGCCGAA AAGGAGAG 7218
1864 UCUCCUUU u GGGCUGCA 1187 UGCAGCCC CUGAUGAGGCCGUUAGGCCGAA AAAGGAGA 7219
1877 UGCAUGCU A UUCCAUUU 1188 AAAUGGAA CUGAUGAGGCCGUUAGGCCGAA AGCAUGCA 7220
1879 CAUGCUAU U CCAUUUUG 1189 CAAAAUGG CUGAUGAGGCCGUUAGGCCGAA AUAGCAUG 7221
1880 AUGCUAUU C CAUUUUGC 1190 GCAAAAUG CUGAUGAGGCCGUUAGGCCGAA AAUAGCAU 7222
1884 UAUUCCAU U UUGCAGCC 1191 GGCUGCAA CUGAUGAGGCCGUUAGGCCGAA AUGGAAUA 7223
1885 AUUCCAUU U UGCAGCCA 1192 UGGCUGCA CUGAUGAGGCCGUUAGGCCGAA AAUGGAAU 7224
1886 UUCCAUUU U GCAGCCAG 1193 CUGGCUGC CUGAUGAGGCCGUUAGGCCGAA AAAUGGAA 7225
1905 CGAUGUGU A UUUAACCA 1194 UGGUUAAA CUGAUGAGGCCGUUAGGCCGAA ACACAUCG 7226
1907 AUGUGUAU U UAACCAGU 1195 ACUGGUUA CUGAUGAGGCCGUUAGGCCGAA AUACACAU 7227
1908 UGUGUAUU U AACCAGUC 1196 GACUGGUU CUGAUGAGGCCGUUAGGCCGAA AAUACACA 7228
1909 GUGUAUUU A ACCAGUCA 1197 UGACUGGU CUGAUGAGGCCGUUAGGCCGAA AAAUACAC 7229
1916 UAACCAGU C ACUAUUGA 1198 UCAAUAGU CUGAUGAGGCCGUUAGGCCGAA ACUGGUUA 7230
1920 CAGUCACU A UUGAUGGA 1199 UCCAUCAA CUGAUGAGGCCGUUAGGCCGAA AGUGACUG 7231
1922 GUCACUAU U GAUGGACA 1200 UGUCCAUC CUGAUGAGGCCGUUAGGCCGAA AUAGUGAC 7232
1932 AUGGACAU U UGGGUUGU 1201 ACAACCCA CUGAUGAGGCCGUUAGGCCGAA AUGUCCAU 7233
1933 UGGACAUU U GGGUUGUU 1202 AACAACCC CUGAUGAGGCCGUUAGGCCGAA AAUGUCCA 7234
1938 AUUUGGGU U GUUUCCCA 1203 UGGGAAAC CUGAUGAGGCCGUUAGGCCGAA ACCCAAAU 7235
1941 UGGGUUGU U UCCCAUCU 1204 AGAUGGGA CUGAUGAGGCCGUUAGGCCGAA ACAACCCA 7236
1942 GGGUUGUU U CCCAUCUU 1205 AAGAUGGG CUGAUGAGGCCGUUAGGCCGAA AACAACCC 7237
1943 GGUUGUUU C CCAUCUUU 1206 AAAGAUGG CUGAUGAGGCCGUUAGGCCGAA AAACAACC 7238
1948 UUUCCCAU C UUUUUGUU 1207 AACAAAAA CUGAUGAGGCCGUUAGGCCGAA AUGGGAAA 7239
1950 UCCCAUCU U UUUGUUAC 1208 GUAACAAA CUGAUGAGGCCGUUAGGCCGAA AGAUGGGA 7240
1951 CCCAUCUU U UUGUUACC 1209 GGUAACAA CUGAUGAGGCCGUUAGGCCGAA AAGAUGGG 7241
1952 CCAUCUUU U UGUUACCA 1210 UGGUAACA CUGAUGAGGCCGUUAGGCCGAA AAAGAUGG 7242
1953 CAUCUUUU U GUUACCAU 1211 AUGGUAAC CUGAUGAGGCCGUUAGGCCGAA AAAAGAUG 7243
1956 CUUUUUGU U ACCAUAAA 1212 UUUAUGGU CUGAUGAGGCCGUUAGGCCGAA ACAAAAAG 7244
1957 UUUUUGUU A CCAUAAAU 1213 AUUUAUGG CUGAUGAGGCCGUUAGGCCGAA AACAAAAA 7245
1962 GUUACCAU A AAUAAUGG 1214 CCAUUAUU CUGAUGAGGCCGUUAGGCCGAA AUGGUAAC 7246
1966 CCAUAAAU A AUGGCAUA 1215 UAUGCCAU CUGAUGAGGCCGUUAGGCCGAA AUUUAUGG 7247
197 AAUGGCAU A GUAAAAAA 1216 UUUUUUAC CUGAUGAGGCCGUUAGGCCGAA AUGCCAUU 7248
1977 GGCAUAGU A AAAAAAAA 1217 UUUUUUUU CUGAUGAGGCCGUUAGGCCGAA ACUAUGCC 7249
Input Sequence = NM_003639. Cut Site = UH/ .
Arm Length = 8. Core Sequence = CUGAUGAG GCCGUUAGGC CGAA
NM_003639 (Homo sapiens inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma (IKBKG), mRNA.; 1994 bp)
Underlined region can be any X sequence or linker, as described herein. Table IX: Human IKK-gamma Inozyme and Substrate Sequence
Pos Substrate Seq Inozyme Seq ID ID
10 GCACGAGC A UGGCCCUU 1218 AAGGGCCA CUGAUGAGGCCGUUAGGCCGAA ICUCGUGC 7250
15 AGCAUGGC C CUUGUGAU 1219 AUCACAAG CUGAUGAGGCCGUUAGGCCGAA ICCAUGCU 7251
16 GCAUGGCC C UUGUGAUC 1220 GAUCACAA CUGAUGAGGCCGUUAGGCCGAA IGCCAUGC 7252
17 CAUGGCCC U UGUGAUCC 1221 GGAUCACA CUGAUGAGGCCGUUAGGCCGAA IGGCCAUG 7253
25 UUGUGAUC C AGGUGGGG 1222 CCCCACCU CUGAUGAGGCCGUUAGGCCGAA IAUCACAA 7254
26 UGUGAUCC A GGUGGGGA 1223 UCCCCACC CUGAUGAGGCCGUUAGGCCGAA IGAUCACA 7255
38 GGGGAAAC U AAGGCCCA 1224 UGGGCCUU CUGAUGAGGCCGUUAGGCCGAA IUUUCCCC 7256
44 ACUAAGGC C CAGAGAAG 1225 CUUCUCUG CUGAUGAGGCCGUUAGGCCGAA ICCUUAGU 7257
45 CUAAGGCC C AGAGAAGU 1226 ACUUCUCU CUGAUGAGGCCGUUAGGCCGAA IGCCUUAG 7258
46 UAAGGCCC A GAGAAGUG 1227 CACUUCUC CUGAUGAGGCCGUUAGGCCGAA IGGCCUUA 7259
60 GUGAGGAC C CCGCAGAC 1228 GUCUGCGG CUGAUGAGGCCGUUAGGCCGAA IUCCUCAC 7260
61 UGAGGACC C CGCAGACU 1229 AGUCUGCG CUGAUGAGGCCGUUAGGCCGAA IGUCCUCA 7261
62 GAGGACCC C GCAGACUA 1230 UAGUCUGC CUGAUGAGGCCGUUAGGCCGAA IGGUCCUC 7262
65 GACCCCGC A GACUAUCA 1231 UGAUAGUC CUGAUGAGGCCGUUAGGCCGAA ICGGGGUC 7263
69 CCGCAGAC U AUCAAUCC 1232 GGAUUGAU CUGAUGAGGCCGUUAGGCCGAA IUCUGCGG 7264
73 AGACUAUC A AUCCCAGU 1233 ACUGGGAU CUGAUGAGGCCGUUAGGCCGAA IAUAGUCU 7265
77 UAUCAAUC C CAGUCUCU 1234 AGAGACUG CUGAUGAGGCCGUUAGGCCGAA IAUUGAUA 7266
78 AUCAAUCC C AGUCUCUU 1235 AAGAGACU CUGAUGAGGCCGUUAGGCCGAA IGAUUGAU 7267
79 UCAAUCCC A GUCUCUUC 1236 GAAGAGAC CUGAUGAGGCCGUUAGGCCGAA IGGAUUGA 7268
83 UCCCAGUC U CUUCCCCU 1237 AGGGGAAG CUGAUGAGGCCGUUAGGCCGAA lACUGGGA 7269
85 CCAGUCUC U UCCCCUCA 1238 UGAGGGGA CUGAUGAGGCCGUUAGGCCGAA IAGACUGG 7270
88 GUCUCUUC C CCUCACUC 1239 GAGUGAGG CUGAUGAGGCCGUUAGGCCGAA IAAGAGAC 7271
89 UCUCUUCC C CUCACUCC 1240 GGAGUGAG CUGAUGAGGCCGUUAGGCCGAA IGAAGAGA 7272
90 cucuuccc C UCACUCCC 1241 GGGAGUGA CUGAUGAGGCCGUUAGGCCGAA IGGAAGAG 7273
91 ucuucccc U CACUCCCU 1242 AGGGAGUG CUGAUGAGGCCGUUAGGCCGAA IGGGAAGA 7274
93 uuccccuc A CUCCCUGU 1243 ACAGGGAG CUGAUGAGGCCGUUAGGCCGAA lAGGGGAA 7275
95 CCCCUCAC U CCCUGUGA 124 UCACAGGG CUGAUGAGGCCGUUAGGCCGAA IUGAGGGG 7276
97 CCUCACUC C CUGUGAAG 1245 CUUCACAG CUGAUGAGGCCGUUAGGCCGAA IAGUGAGG 7277
98 CUCACUCC C UGUGAAGC 1246 GCUUCACA CUGAUGAGGCCGUUAGGCCGAA IGAGUGAG 7278
99 UCACUCCC U GUGAAGCU 1247 AGCUUCAC CUGAUGAGGCCGUUAGGCCGAA IGGAGUGA 7279
107 UGUGAAGC U CUCCAGCA 1248 UGCUGGAG CUGAUGAGGCCGUUAGGCCGAA ICUUCACA 7280
109 UGAAGCUC U CCAGCAUC 1249 GAUGCUGG CUGAUGAGGCCGUUAGGCCGAA IAGCUUCA 7281
111 AAGCUCUC C AGCAUCAU 1250 AUGAUGCU CUGAUGAGGCCGUUAGGCCGAA IAGAGCUU 7282
112 AGCUCUCC A GCAUCAUC 1251 GAUGAUGC CUGAUGAGGCCGUUAGGCCGAA IGAGAGCU 7283
115 UCUCCAGC A UCAUCGAG 1252 CUCGAUGA CUGAUGAGGCCGUUAGGCCGAA ICUGGAGA 7284
118 CCAGCAUC A UCGAGGUC 1253 GACCUCGA CUGAUGAGGCCGUUAGGCCGAA IAUGCUGG 7285
127 UCGAGGUC C CAUCAGCC 1254 GGCUGAUG CUGAUGAGGCCGUUAGGCCGAA IACCUCGA 7286
128 CGAGGUCC C AUCAGCCC 1255 GGGCUGAU CUGAUGAGGCCGUUAGGCCGAA IGACCUCG 7287
129 GAGGUCCC A UCAGCCCU 1256 AGGGCUGA CUGAUGAGGCCGUUAGGCCGAA IGGACCUC 7288
132 GUCCCAUC A GCCCUUGC 1257 GCAAGGGC CUGAUGAGGCCGUUAGGCCGAA IAUGGGAC 7289
135 CCAUCAGC C CUUGCCCU 1258 AGGGCAAG CUGAUGAGGCCGUUAGGCCGAA ICUGAUGG 7290
136 CAUCAGCC c UUGCCCUG 1259 CAGGGCAA CUGAUGAGGCCGUUAGGCCGAA IGCUGAUG 7291
137 AUGAGCCC u UGCCCUGU 1260 ACAGGGCA CUGAUGAGGCCGUUAGGCCGAA IGGCUGAU 7292
141 GCCCUUGC c CUGUUGGA 1261 UCCAACAG CUGAUGAGGCCGUUAGGCCGAA ICAAGGGC 7293
142 CCCUUGCC c UGUUGGAU 1262 AUCCAACA CUGAUGAGGCCGUUAGGCCGAA IGCAAGGG 729
143 CCUUGCCC u GUUGGAUG 1263 CAUCCAAC CUGAUGAGGCCGUUAGGCCGAA IGGCAAGG 7295
159 GAAUAGGC A CCUCUGGA 1264 UCCAGAGG CUGAUGAGGCCGUUAGGCCGAA ICCUAUUC 7296 161 AUAGGCAC C UCUGGAAG 1265 CUUCCAGA CUGAUGAGGCCGUUAGGCCGAA IUGCCUAU 7297
162 UAGGCACC U CUGGAAGA 1266 UCUUCCAG CUGAUGAGGCCGUUAGGCCGAA IGUGCCUA 7298
164 GGCACCUC U GGAAGAGC 1267 GCUCUUCC CUGAUGAGGCCGUUAGGCCGAA IAGGUGCC 7299
173 GGAAGAGC C AACUGUGU 1268 ACACAGUU CUGAUGAGGCCGUUAGGCCGAA ICUCUUCC 7300
174 GAAGAGCC A ACUGUGUG 1269 CACACAGU CUGAUGAGGCCGUUAGGCCGAA IGCUCUUC 7301
177 GAGCCAAC U GUGUGAGA 1270 UCUCACAC CUGAUGAGGCCGUUAGGCCGAA IUUGGCUC 7302
192 GAUGGUGC A GCCCAGUG 1271 CACUGGGC CUGAUGAGGCCGUUAGGCCGAA ICACCAUC 7303
195 GGUGCAGC C CAGUGGUG 1272 CACCACUG CUGAUGAGGCCGUUAGGCCGAA ICUGCACC 7304
196 GUGCAGCC C AGUGGUGG 1273 CCACCACU CUGAUGAGGCCGUUAGGCCGAA IGCUGCAC 7305
197 UGCAGCCC A GUGGUGGC 1274 GCCACCAC CUGAUGAGGCCGUUAGGCCGAA IGGCUGCA 7306
206 GUGGUGGC C CGGCAGCA 1275 UGCUGCCG CUGAUGAGGCCGUUAGGCCGAA ICCACCAC 7307
207 UGGUGGCC C GGCAGCAG 1276 CUGCUGCC CUGAUGAGGCCGUUAGGCCGAA IGCCACCA 7308
211 GGCCCGGC A GCAGAUCA 1277 UGAUCUGC CUGAUGAGGCCGUUAGGCCGAA ICCGGGCC 7309
214 CCGGCAGC A GAUCAGGA 1278 UCCUGAUC CUGAUGAGGCCGUUAGGCCGAA ICUGCCGG 7310
219 AGCAGAUC A GGACGUAC 1279 GUACGUCC CUGAUGAGGCCGUUAGGCCGAA IAUCUGCU 7311
228 GGACGUAC U GGGCGAAG 1280 CUUCGCCC CUGAUGAGGCCGUUAGGCCGAA IUACGUCC 7312
241 GAAGAGUC U CCUCUGGG 1281 CCCAGAGG CUGAUGAGGCCGUUAGGCCGAA IACUCUUC 7313
243 AGAGUCUC C UCUGGGGA 1282 UCCCCAGA CUGAUGAGGCCGUUAGGCCGAA IAGACUCU 7314
244 GAGUCUCC U CUGGGGAA 1283 UUCCCCAG CUGAUGAGGCCGUUAGGCCGAA IGAGACUC 7315
246 GUCUCCUC U GGGGAAGC 1284 GCUUCCCC CUGAUGAGGCCGUUAGGCCGAA IAGGAGAC 7316
255 GGGGAAGC C AGCCAUGC 1285 GCAUGGCU CUGAUGAGGCCGUUAGGCCGAA ICUUCCCC 7317
256 GGGAAGCC A GCCAUGCU 1286 AGCAUGGC CUGAUGAGGCCGUUAGGCCGAA IGCUUCCC 7318
259 AAGCCAGC C AUGCUGCA 1287 UGCAGCAU CUGAUGAGGCCGUUAGGCCGAA ICUGGCUU 7319
260 AGCCAGCC A UGCUGCAC 1288 GUGCAGCA CUGAUGAGGCCGUUAGGCCGAA IGCUGGCU 7320
264 AGCCAUGC U GCACCUGC 1289 GCAGGUGC CUGAUGAGGCCGUUAGGCCGAA ICAUGGCU 7321
267 CAUGCUGC A CCUGCCUU 1290 AAGGCAGG CUGAUGAGGCCGUUAGGCCGAA ICAGCAUG 7322
269 UGCUGCAC C UGCCUUCA 1291 UGAAGGCA CUGAUGAGGCCGUUAGGCCGAA lUGCAGCA 7323
270 GCUGCACC U GCCUUCAG 1292 CUGAAGGC CUGAUGAGGCCGUUAGGCCGAA IGUGCAGC 7324
273 GCACCUGC C UUCAGAAC 1293 GUUCUGAA CUGAUGAGGCCGUUAGGCCGAA ICAGGUGC 7325
274 CACCUGCC U UCAGAACA 1294 UGUUCUGA CUGAUGAGGCCGUUAGGCCGAA IGCAGGUG 7326
277 CUGCCUUC A GAACAGGG 1295 CCCUGUUC CUGAUGAGGCCGUUAGGCCGAA IAAGGCAG 7327
282 UUCAGAAC A GGGCGCUC 1296 GAGCGCCC CUGAUGAGGCCGUUAGGCCGAA IUUCUGAA 7328
289 CAGGGCGC U CCUGAGAC 1297 GUCUCAGG CUGAUGAGGCCGUUAGGCCGAA ICGCCCUG 7329
291 GGGCGCUC C UGAGACCC 1298 GGGUCUCA CUGAUGAGGCCGUUAGGCCGAA IAGCGCCC 7330
292 GGCGCUCC U GAGACCCU 1299 AGGGUCUC CUGAUGAGGCCGUUAGGCCGAA IGAGCGCC 7331
298 CCUGAGAC C CUCCAGCG 1300 CGCUGGAG CUGAUGAGGCCGUUAGGCCGAA IUCUCAGG 7332
299 CUGAGACC C UCCAGCGC 1301 GCGCUGGA CUGAUGAGGCCGUUAGGCCGAA IGUCUCAG 7333
300 UGAGACCC U CCAGCGCU 1302 AGCGCUGG CUGAUGAGGCCGUUAGGCCGAA IGGUCUCA 7334
302 AGACCCUC C AGCGCUGC 1303 GCAGCGCU CUGAUGAGGCCGUUAGGCCGAA IAGGGUCU 7335
303 GACCCUCC A GCGCUGCC 1304 GGCAGCGC CUGAUGAGGCCGUUAGGCCGAA IGAGGGUC 7336
308 UCCAGCGC U GCCUGGAG 1305 CUCCAGGC CUGAUGAGGCCGUUAGGCCGAA ICGCUGGA 7337
311 AGCGCUGC C UGGAGGAG 1306 CUCCUCCA CUGAUGAGGCCGUUAGGCCGAA ICAGCGCU 7338
312 GCGCUGCC U GGAGGAGA 1307 UCUCCUCC CUGAUGAGGCCGUUAGGCCGAA IGCAGCGC 7339
324 GGAGAAUC A AGAGCUCC 1308 GGAGCUCU CUGAUGAGGCCGUUAGGCCGAA IAUUCUCC 7340
330 UCAAGAGC U CCGAGAUG 1309 CAUCUCGG CUGAUGAGGCCGUUAGGCCGAA ICUCUUGA 7341
332 AAGAGCUC C GAGAUGCC 1310 GGCAUCUC CUGAUGAGGCCGUUAGGCCGAA IAGCUCUU 7342
340 CGAGAUGC C AUCCGGCA 1311 UGCCGGAU CUGAUGAGGCCGUUAGGCCGAA ICAUCUCG 7343
341 GAGAUGCC A UCCGGCAG 1312 CUGCCGGA CUGAUGAGGCCGUUAGGCCGAA IGCAUCUC 7344
344 AUGCCAUC C GGCAGAGC 1313 GCUCUGCC CUGAUGAGGCCGUUAGGCCGAA IAUGGCAU 7345
348 CAUCCGGC A GAGCAACC 1314 GGUUGCUC CUGAUGAGGCCGUUAGGCCGAA ICCGGAUG 7346
353 GGCAGAGC A ACCAGAUU 1315 AAUCUGGU CUGAUGAGGCCGUUAGGCCGAA ICUCUGCC 7347 356 AGAGCAAC C AGAUUCUG 1316 CAGAAUCU CUGAUGAGGCCGUUAGGCCGAA IUUGCUCU 7348
357 GAGCAACC A GAUUCUGC 1317 GCAGAAUC CUGAUGAGGCCGUUAGGCCGAA IGUUGCUC 7349
363 CCAGAUUC U GCGGGAGC 1318 GCUCCCGC CUGAUGAGGCCGUUAGGCCGAA IAAUCUGG 7350
374 GGGAGCGC U GCGAGGAG 1319 CUCCUCGC CUGAUGAGGCCGUUAGGCCGAA ICGCUCCC 7351
384 CGAGGAGC U UCUGCAUU 1320 AAUGCAGA CUGAUGAGGCCGUUAGGCCGAA ICUCCUCG 7352
387 GGAGCUUC U GCAUUUCC 1321 GGAAAUGC CUGAUGAGGCCGUUAGGCCGAA IAAGCUCC 7353
390 GCUUCUGC A UUUCCAAG 1322 CUUGGAAA CUGAUGAGGCCGUUAGGCCGAA ICAGAAGC 7354
395 UGCAUUUC C AAGCCAGC 1323 GCUGGCUU CUGAUGAGGCCGUUAGGCCGAA lAAAUGCA 7355
396 GCAUUUCC A AGCCAGCC 1324 GGCUGGCU CUGAUGAGGCCGUUAGGCCGAA IGAAAUGC 7356
400 UUCCAAGC C AGCCAGAG 1325 CUCUGGCU CUGAUGAGGCCGUUAGGCCGAA ICUUGGAA 7357
401 UCCAAGCC A GCCAGAGG 1326 CCUCUGGC CUGAUGAGGCCGUUAGGCCGAA IGCUUGGA 7358
404 AAGCCAGC C AGAGGGAG 1327 CUCCCUCU CUGAUGAGGCCGUUAGGCCGAA ICUGGCUU 7359
405 AGCCAGCC A GAGGGAGG 1328 CCUCCCUC CUGAUGAGGCCGUUAGGCCGAA IGCUGGCU 7360
425 AGGAGUUC C UCAUGUGC 1329 GCACAUGA CUGAUGAGGCCGUUAGGCCGAA IAACUCCU 7361
426 GGAGUUCC U CAUGUGCA 1330 UGCACAUG CUGAUGAGGCCGUUAGGCCGAA IGAACUCC 7362
428 AGUUCCUC A UGUGCAAG 1331 CUUGCACA CUGAUGAGGCCGUUAGGCCGAA IAGGAACU 7363
434 UCAUGUGC A AGUUCCAG 1332 CUGGAACU CUGAUGAGGCCGUUAGGCCGAA ICACAUGA 7364
440 GCAAGUUC C AGGAGGCC 1333 GGCCUCCU CUGAUGAGGCCGUUAGGCCGAA IAACUUGC 7365
441 CAAGUUCC A GGAGGCCA 1334 UGGCCUCC CUGAUGAGGCCGUUAGGCCGAA IGAACUUG 7366
448 CAGGAGGC C AGGAAACU 1335 AGUUUCCU CUGAUGAGGCCGUUAGGCCGAA ICCUCCUG 7367
449 AGGAGGCC A GGAAACUG 1336 CAGUUUCC CUGAUGAGGCCGUUAGGCCGAA IGCCUCCU 7368
456 CAGGAAAC U GGUGGAGA 1337 UCUCCACC CUGAUGAGGCCGUUAGGCCGAA IUUUCCUG 7369
468 GGAGAGAC U CGGCCUGG 1338 CCAGGCCG CUGAUGAGGCCGUUAGGCCGAA IUCUCUCC 7370
473 GACUCGGC C UGGAGAAG 1339 CUUCUCCA CUGAUGAGGCCGUUAGGCCGAA ICCGAGUC 7371
474 ACUCGGCC U GGAGAAGC 1340 GCUUCUCC CUGAUGAGGCCGUUAGGCCGAA IGCCGAGU 7372
483 GGAGAAGC U CGAUCUGA 1341 UCAGAUCG CUGAUGAGGCCGUUAGGCCGAA ICUUCUCC 7373
489 GCUCGAUC U GAAGAGGC 1342 GCCUCUUC CUGAUGAGGCCGUUAGGCCGAA IAUCGAGC 7374
498 GAAGAGGC A GAAGGAGC 1343 GCUCCUUC CUGAUGAGGCCGUUAGGCCGAA ICCUCUUC 7375
507 GAAGGAGC A GGCUCUGC 1344 GCAGAGCC CUGAUGAGGCCGUUAGGCCGAA ICUCCUUC 7376
511 GAGCAGGC U CUGCGGGA 1345 UCCCGCAG CUGAUGAGGCCGUUAGGCCGAA ICCUGCUC 7377
513 GCAGGCUC U GCGGGAGG 1346 CCUCCCGC CUGAUGAGGCCGUUAGGCCGAA IAGCCUGC 7378
528 GGUGGAGC A CCUGAAGA 1347 UCUUCAGG CUGAUGAGGCCGUUAGGCCGAA ICUCCACC 7379
530 UGGAGCAC C UGAAGAGA 1348 UCUCUUCA CUGAUGAGGCCGUUAGGCCGAA lUGCUCCA 7380
531 GGAGCACC U GAAGAGAU 1349 AUCUCUUC CUGAUGAGGCCGUUAGGCCGAA IGUGCUCC 7381
542 AGAGAUGC C AGCAGCAG 1350 CUGCUGCU CUGAUGAGGCCGUUAGGCCGAA ICAUCUCU 7382
543 GAGAUGCC A GCAGCAGA 1351 UCUGCUGC CUGAUGAGGCCGUUAGGCCGAA IGCAUCUC 7383
546 AUGCCAGC A GCAGAUGG 1352 CCAUCUGC CUGAUGAGGCCGUUAGGCCGAA ICUGGCAU 7384
549 CCAGCAGC A GAUGGCUG 1353 CAGCCAUC CUGAUGAGGCCGUUAGGCCGAA ICUGCUGG 7385
556 CAGAUGGC U GAGGACAA 1354 UUGUCCUC CUGAUGAGGCCGUUAGGCCGAA ICCAUCUG 7386
563 CUGAGGAC A AGGCCUCU 1355 AGAGGCCU CUGAUGAGGCCGUUAGGCCGAA IUCCUCAG 7387
568 GACAAGGC C UCUGUGAA 1356 UUCACAGA CUGAUGAGGCCGUUAGGCCGAA ICCUUGUC 7388
569 ACAAGGCC U CUGUGAAA 1357 UUUCACAG CUGAUGAGGCCGUUAGGCCGAA IGCCUUGU 7389
571 AAGGCCUC U GUGAAAGC 1358 GCUUUCAC CUGAUGAGGCCGUUAGGCCGAA IAGGCCUU 7390
580 GUGAAAGC C CAGGUGAC 1359 GUCACCUG CUGAUGAGGCCGUUAGGCCGAA ICUUUCAC 7391
581 UGAAAGCC C AGGUGACG 1360 CGUCACCU CUGAUGAGGCCGUUAGGCCGAA IGCUUUCA 7392
582 GAAAGCCC A GGUGACGU 1361 ACGUCACC CUGAUGAGGCCGUUAGGCCGAA IGGCUUUC 7393
592 GUGACGUC C UUGCUCGG 1362 CCGAGCAA CUGAUGAGGCCGUUAGGCCGAA IACGUCAC 7394
593 UGACGUCC U UGCUCGGG 1363 CCCGAGCA CUGAUGAGGCCGUUAGGCCGAA IGACGUCA 7395
597 GUCCUUGC U CGGGGAGC 1364 GCUCCCCG CUGAUGAGGCCGUUAGGCCGAA ICAAGGAC 7396
606 CGGGGAGC U GCAGGAGA 1365 UCUCCUGC CUGAUGAGGCCGUUAGGCCGAA ICUCCCCG 7397
609 GGAGCUGC A GGAGAGCC 1366 GGCUCUCC CUGAUGAGGCCGUUAGGCCGAA ICAGCUCC 7398 617 AGGAGAGC C AGAGUCGC 1367 GCGACUCU CUGAUGAGGCCGUUAGGCCGAA ICUCUCCU 7399
618 GGAGAGCC A GAGUCGCU 1368 AGCGACUC CUGAUGAGGCCGUUAGGCCGAA IGCUCUCC 7400
626 AGAGUCGC U UGGAGGCU 1369 AGCCUCCA CUGAUGAGGCCGUUAGGCCGAA ICGACUCU 7401
634 UUGGAGGC U GCCACUAA 1370 UUAGUGGC CUGAUGAGGCCGUUAGGCCGAA ICCUCCAA 7402
637 GAGGCUGC C ACUAAGGA 1371 UCCUUAGU CUGAUGAGGCCGUUAGGCCGAA ICAGCCUC 7403
638 AGGCUGCC A CUAAGGAA 1372 UUCCUUAG CUGAUGAGGCCGUUAGGCCGAA IGCAGCCU 7404
640 GCUGCCAC U AAGGAAUG 1373 CAUUCCUU CUGAUGAGGCCGUUAGGCCGAA IUGGCAGC 7405
650 AGGAAUGC C AGGCUCUG 1374 CAGAGCCU CUGAUGAGGCCGUUAGGCCGAA ICAUUCCU 7406
651 GGAAUGCC A GGCUCUGG 1375 CCAGAGCC CUGAUGAGGCCGUUAGGCCGAA IGCAUUCC 7407
655 UGCCAGGC U CUGGAGGG 1376 CCCUCCAG CUGAUGAGGCCGUUAGGCCGAA ICCUGGCA 7408
657 CCAGGCUC U GGAGGGUC 1377 GACCCUCC CUGAUGAGGCCGUUAGGCCGAA IAGCCUGG 7409
670 GGUCGGGC C CGGGCGGC 1378 GCCGCCCG CUGAUGAGGCCGUUAGGCCGAA ICCCGACC 7410
671 GUCGGGCC C GGGCGGCC 1379 GGCCGCCC CUGAUGAGGCCGUUAGGCCGAA IGCCCGAC 7411
679 CGGGCGGC C AGCGAGCA 1380 UGCUCGCU CUGAUGAGGCCGUUAGGCCGAA ICCGCCCG 7412
680 GGGCGGCC A GCGAGCAG 1381 CUGCUCGC CUGAUGAGGCCGUUAGGCCGAA IGCCGCCC 7413
687 CAGCGAGC A GGCGCGGC 1382 GCCGCGCC CUGAUGAGGCCGUUAGGCCGAA ICUCGCUG 7414
696 GGCGCGGC A GCUGGAGA 1383 UCUCCAGC CUGAUGAGGCCGUUAGGCCGAA ICCGCGCC 7415
699 GCGGCAGC U GGAGAGUG 1384 CACUCUCC CUGAUGAGGCCGUUAGGCCGAA ICUGCCGC 7416
720 CGAGGCGC U GCAGCAGC 1385 GCUGCUGC CUGAUGAGGCCGUUAGGCCGAA ICGCCUCG 7417
723 GGCGCUGC A GCAGCAGC 1386 GCUGCUGC CUGAUGAGGCCGUUAGGCCGAA ICAGCGCC 7418
726 GCUGCAGC A GCAGCACA 1387 UGUGCUGC CUGAUGAGGCCGUUAGGCCGAA ICUGCAGC 7419
729 GCAGCAGC A GCACAGCG 1388 CGCUGUGC CUGAUGAGGCCGUUAGGCCGAA ICUGCUGC 7420
732 GCAGCAGC A CAGCGUGC 1389 GCACGCUG CUGAUGAGGCCGUUAGGCCGAA ICUGCUGC 7421
734 AGCAGCAC A GCGUGCAG 1390 CUGCACGC CUGAUGAGGCCGUUAGGCCGAA IUGCUGCU 7422
741 CAGCGUGC A GGUGGACC 1391 GGUCCACC CUGAUGAGGCCGUUAGGCCGAA ICACGCUG 7423
749 AGGUGGAC C AGCUGCGC 1392 GCGCAGCU CUGAUGAGGCCGUUAGGCCGAA IUCCACCU 7424
750 GGUGGACC A GCUGCGCA 1393 UGCGCAGC CUGAUGAGGCCGUUAGGCCGAA IGUCCACC 7425
753 GGACCAGC U GCGCAUGC 1394 GCAUGCGC CUGAUGAGGCCGUUAGGCCGAA ICUGGUCC 7426
758 AGCUGCGC A UGCAGGGC 1395 GCCCUGCA CUGAUGAGGCCGUUAGGCCGAA ICGCAGCU 7427
762 GCGCAUGC A GGGCCAGA 1396 UCUGGCCC CUGAUGAGGCCGUUAGGCCGAA ICAUGCGC 7428
767 UGCAGGGC C AGAGCGUG 1397 CACGCUCU CUGAUGAGGCCGUUAGGCCGAA ICCCUGCA 7429
768 GCAGGGCC A GAGCGUGG 1398 CCACGCUC CUGAUGAGGCCGUUAGGCCGAA IGCCCUGC 7430
781 GUGGAGGC C GCGCUCCG 1399 CGGAGCGC CUGAUGAGGCCGUUAGGCCGAA ICCUCCAC 7431
786 GGCCGCGC U CCGCAUGG 1400 CCAUGCGG CUGAUGAGGCCGUUAGGCCGAA ICGCGGCC 7432
788 CCGCGCUC C GCAUGGAG 1401 CUCCAUGC CUGAUGAGGCCGUUAGGCCGAA IAGCGCGG 7433
791 CGCUCCGC A UGGAGCGC 1402 GCGCUCCA CUGAUGAGGCCGUUAGGCCGAA ICGGAGCG 7434
800 UGGAGCGC C AGGCCGCC 1403 GGCGGCCU CUGAUGAGGCCGUUAGGCCGAA ICGCUCCA 7435
801 GGAGCGCC A GGCCGCCU 1404 AGGCGGCC CUGAUGAGGCCGUUAGGCCGAA IGCGCUCC 7436
805 CGCCAGGC C GCCUCGGA 1405 UCCGAGGC CUGAUGAGGCCGUUAGGCCGAA ICCUGGCG 7437
808 CAGGCCGC C UCGGAGGA 1406 UCCUCCGA CUGAUGAGGCCGUUAGGCCGAA ICGGCCUG 7438
809 AGGCCGCC U CGGAGGAG 1407 CUCCUCCG CUGAUGAGGCCGUUAGGCCGAA IGCGGCCU 7439
828 GAGGAAGC U GGCCCAGU 1408 ACUGGGCC CUGAUGAGGCCGUUAGGCCGAA ICUUCCUC 7440
832 AAGCUGGC C CAGUUGCA 1409 UGCAACUG CUGAUGAGGCCGUUAGGCCGAA ICCAGCUU 7441
833 AGCUGGCC C AGUUGCAG 1410 CUGCAACU CUGAUGAGGCCGUUAGGCCGAA IGCCAGCU 7442
834 GCUGGCCC A GUUGCAGG 1411 CCUGCAAC CUGAUGAGGCCGUUAGGCCGAA IGGCCAGC 7443
840 CCAGUUGC A GGUGGCCU 1412 AGGCCACC CUGAUGAGGCCGUUAGGCCGAA ICAACUGG 7444
847 CAGGUGGC C UAUCACCA 1413 UGGUGAUA CUGAUGAGGCCGUUAGGCCGAA ICCACCUG 7445
848 AGGUGGCC U AUCACCAG 1414 CUGGUGAU CUGAUGAGGCCGUUAGGCCGAA IGCCACCU 7446
852 GGCCUAUC A CCAGCUCU 1415 AGAGCUGG CUGAUGAGGCCGUUAGGCCGAA IAUAGGCC 7447
854 CCUAUCAC C AGCUCUUC 1416 GAAGAGCU CUGAUGAGGCCGUUAGGCCGAA IUGAUAGG 7448
855 CUAUCACC A GCUCUUCC 1417 GGAAGAGC CUGAUGAGGCCGUUAGGCCGAA IGUGAUAG 7449 858 UCACCAGC U CUUCCAAG 1418 CUUGGAAG CUGAUGAGGCCGUUAGGCCGAA ICUGGUGA 7450
860 ACCAGCUC U UCCAAGAA 1419 UUCUUGGA CUGAUGAGGCCGUUAGGCCGAA IAGCUGGU 7451
863 AGCUCUUC C AAGAAUAC 1420 GUAUUCUU CUGAUGAGGCCGUUAGGCCGAA IAAGAGCU 7452
864 GCUCUUCC A AGAAUACG 1421 CGUAUUCU CUGAUGAGGCCGUUAGGCCGAA IGAAGAGC 7453
875 AAUACGAC A ACCACAUC 1422 GAUGUGGU CUGAUGAGGCCGUUAGGCCGAA IUCGUAUU 7454
878 ACGACAAC C ACAUCAAG 1423 CUUGAUGU CUGAUGAGGCCGUUAGGCCGAA IUUGUCGU 7455
879 CGACAACC A CAUCAAGA 1424 UCUUGAUG CUGAUGAGGCCGUUAGGCCGAA IGUUGUCG 7456
881 ACAACCAC A UCAAGAGC 1425 GCUCUUGA CUGAUGAGGCCGUUAGGCCGAA IUGGUUGU 7457
884 ACCACAUC A AGAGCAGC 1426 GCUGCUCU CUGAUGAGGCCGUUAGGCCGAA IAUGUGGU 7458
890 UCAAGAGC A GCGUGGUG 1427 CACCACGC CUGAUGAGGCCGUUAGGCCGAA ICUCUUGA 7459
902 UGGUGGGC A GUGAGCGG 1428 CCGCUCAC CUGAUGAGGCCGUUAGGCCGAA ICCCACCA 7460
924 AGGAAUGC A GCUGGAAG 1429 CUUCCAGC CUGAUGAGGCCGUUAGGCCGAA ICAUUCCU 7461
927 AAUGCAGC U GGAAGAUC 1430 GAUCUUCC CUGAUGAGGCCGUUAGGCCGAA ICUGCAUU 7462
936 GGAAGAUC U CAAACAGC 1431 GCUGUUUG CUGAUGAGGCCGUUAGGCCGAA IAUCUUCC 7463
938 AAGAUCUC A AACAGCAG 1432 CUGCUGUU CUGAUGAGGCCGUUAGGCCGAA IAGAUCUU 7464
942 UCUCAAAC A GCAGCUCC 1433 GGAGCUGC CUGAUGAGGCCGUUAGGCCGAA IUUUGAGA 7465
945 CAAACAGC A GCUCCAGC 1434 GCUGGAGC CUGAUGAGGCCGUUAGGCCGAA ICUGUUUG 7466
948 ACAGCAGC U CCAGCAGG 1435 CCUGCUGG CUGAUGAGGCCGUUAGGCCGAA ICUGCUGU 7467
950 AGCAGCUC C AGCAGGCC 1436 GGCCUGCU CUGAUGAGGCCGUUAGGCCGAA IAGCUGCU 7468
951 GCAGCUCC A GCAGGCCG 1437 CGGCCUGC CUGAUGAGGCCGUUAGGCCGAA IGAGCUGC 7469
954 GCUCCAGC A GGCCGAGG 1438 CCUCGGCC CUGAUGAGGCCGUUAGGCCGAA ICUGGAGC 7470
958 CAGCAGGC C GAGGAGGC 1439 GCCUCCUC CUGAUGAGGCCGUUAGGCCGAA ICCUGCUG 7471
967 GAGGAGGC C CUGGUGGC 1440 GCCACCAG CUGAUGAGGCCGUUAGGCCGAA ICCUCCUC 7472
968 AGGAGGCC C UGGUGGCC 1441 GGCCACCA CUGAUGAGGCCGUUAGGCCGAA IGCCUCCU 7473
969 GGAGGCCC U GGUGGCCA 1442 UGGCCACC CUGAUGAGGCCGUUAGGCCGAA IGGCCUCC 7474
976 CUGGUGGC C AAACAGGA 1443 UCCUGUUU CUGAUGAGGCCGUUAGGCCGAA ICCACCAG 7475
977 UGGUGGCC A AACAGGAG 1444 CUCCUGUU CUGAUGAGGCCGUUAGGCCGAA IGCCACCA 7476
981 GGCCAAAC A GGAGGUGA 1445 UCACCUCC CUGAUGAGGCCGUUAGGCCGAA IUUUGGCC 7477
999 CGAUAAGC U GAAGGAGG 1446 CCUCCUUC CUGAUGAGGCCGUUAGGCCGAA ICUUAUCG 7478
1012 GAGGAGGC C GAGCAGCA 1447 UGCUGCUC CUGAUGAGGCCGUUAGGCCGAA ICCUCCUC 7479
1017 GGCCGAGC A GCACAAGA 1448 UCUUGUGC CUGAUGAGGCCGUUAGGCCGAA ICUCGGCC 7480
1020 CGAGCAGC A CAAGAUUG 1449 CAAUCUUG CUGAUGAGGCCGUUAGGCCGAA ICUGCUCG 7481
1022 AGCAGCAC A AGAUUGUG 1450 CACAAUCU CUGAUGAGGCCGUUAGGCCGAA IUGCUGCU 7482
1039 AUGGAGAC C GUUCCGGU 1451 ACCGGAAC CUGAUGAGGCCGUUAGGCCGAA lUCUCCAU 7483
1044 GACCGUUC C GGUGCUGA 1452 UCAGCACC CUGAUGAGGCCGUUAGGCCGAA IAACGGUC 7484
1050 UCCGGUGC U GAAGGCCC 1453 GGGCCUUC CUGAUGAGGCCGUUAGGCCGAA ICACCGGA 7485
1057 CUGAAGGC C CAGGCGGA 1454 UCCGCCUG CUGAUGAGGCCGUUAGGCCGAA ICCUUCAG 7486
1058 UGAAGGCC C AGGCGGAU 1455 AUCCGCCU CUGAUGAGGCCGUUAGGCCGAA IGCCUUCA 7487
1059 GAAGGCCC A GGCGGAUA 1456 UAUCCGCC CUGAUGAGGCCGUUAGGCCGAA IGGCCUUC 7488
1070 CGGAUAUC U ACAAGGCG 1457 CGCCUUGU CUGAUGAGGCCGUUAGGCCGAA IAUAUCCG 7489
1073 AUAUCUAC A AGGCGGAC 1458 GUCCGCCU CUGAUGAGGCCGUUAGGCCGAA IUAGAUAU 7490
1082 AGGCGGAC U UCCAGGCU 1459 AGCCUGGA CUGAUGAGGCCGUUAGGCCGAA IUCCGCCU 7491
1085 CGGACUUC C AGGCUGAG 1460 CUCAGCCU CUGAUGAGGCCGUUAGGCCGAA IAAGUCCG 7492
1086 GGACUUCC A GGCUGAGA 1461 UCUCAGCC CUGAUGAGGCCGUUAGGCCGAA IGAAGUCC 7493
1090 UUCCAGGC U GAGAGGCA 1462 UGCCUCUC CUGAUGAGGCCGUUAGGCCGAA ICCUGGAA 7494
1098 UGAGAGGC A GGCCCGGG 1463 CCCGGGCC CUGAUGAGGCCGUUAGGCCGAA ICCUCUCA 7495
1102 AGGCAGGC C CGGGAGAA 1464 UUCUCCCG CUGAUGAGGCCGUUAGGCCGAA ICCUGCCU 7496
1103 GGCAGGCC C GGGAGAAG 1465 CUUCUCCC CUGAUGAGGCCGUUAGGCCGAA IGCCUGCC 7497
1113 GGAGAAGC U GGCCGAGA 1466 UCUCGGCC CUGAUGAGGCCGUUAGGCCGAA ICUUCUCC 7498
1117 AAGCUGGC C GAGAAGAA 1467 UUCUUCUC CUGAUGAGGCCGUUAGGCCGAA ICCAGCUU 7499
1131 GAAGGAGC U CCUGCAGG 1468 CCUGCAGG CUGAUGAGGCCGUUAGGCCGAA ICUCCUUC 7500 1133 AGGAGCUC c UGCAGGAG 1469 CUCCUGCA CUGAUGAGGCCGUUAGGCCGAA IAGCUCCU 7501
1134 GGAGCUCC u GCAGGAGC 1470 GCUCCUGC CUGAUGAGGCCGUUAGGCCGAA IGAGCUCC 7502
1137 GCUCCUGC A GGAGCAGC 1471 GCUGCUCC CUGAUGAGGCCGUUAGGCCGAA ICAGGAGC 7503
1143 GCAGGAGC A GCUGGAGC 1472 GCUCCAGC CUGAUGAGGCCGUUAGGCCGAA ICUCCUGC 7504
1146 GGAGCAGC U GGAGCAGC 1473 GCUGCUCC CUGAUGAGGCCGUUAGGCCGAA ICUGCUCC 7505
1152 GCUGGAGC A GCUGCAGA 1474 UCUGCAGC CUGAUGAGGCCGUUAGGCCGAA ICUCCAGC 7506
1155 GGAGCAGC U GCAGAGGG 1475 CCCUCUGC CUGAUGAGGCCGUUAGGCCGAA ICUGCUCC 7507
1158 GCAGCUGC A GAGGGAGU 1476 ACUCCCUC CUGAUGAGGCCGUUAGGCCGAA ICAGCUGC 7508
1169 GGGAGUAC A GCAAACUG 1477 CAGUUUGC CUGAUGAGGCCGUUAGGCCGAA IUACUCCC 7509
1172 AGUACAGC A AACUGAAG 1478 CUUCAGUU CUGAUGAGGCCGUUAGGCCGAA ICUGUACU 7510
1176 CAGCAAAC U GAAGGCCA 1479 UGGCCUUC CUGAUGAGGCCGUUAGGCCGAA IUUUGCUG 7511
1183 CUGAAGGC C AGCUGUCA 1480 UGACAGCU CUGAUGAGGCCGUUAGGCCGAA ICCUUCAG 7512
1184 UGAAGGCC A GCUGUCAG 1481 CUGACAGC CUGAUGAGGCCGUUAGGCCGAA IGCCUUCA 7513
1187 AGGCCAGC U GUCAGGAG 1482 CUCCUGAC CUGAUGAGGCCGUUAGGCCGAA ICUGGCCU 7514
1191 CAGCUGUC A GGAGUCGG 1483 CCGACUCC CUGAUGAGGCCGUUAGGCCGAA IACAGCUG 7515
1201 GAGUCGGC C AGGAUCGA 1484 UCGAUCCU CUGAUGAGGCCGUUAGGCCGAA ICCGACUC 7516
1202 AGUCGGCC A GGAUCGAG 1485 CUCGAUCC CUGAUGAGGCCGUUAGGCCGAA IGCCGACU 7517
1214 UCGAGGAC A UGAGGAAG 1486 CUUCCUCA CUGAUGAGGCCGUUAGGCCGAA IUCCUCGA 7518
1227 GAAGCGGC A UGUCGAGG 1487 CCUCGACA CUGAUGAGGCCGUUAGGCCGAA ICCGCUUC 7519
1238 UCGAGGUC U CCCAGGCC 1488 GGCCUGGG CUGAUGAGGCCGUUAGGCCGAA IACCUCGA 7520
1240 GAGGUCUC C CAGGCCCC 1489 GGGGCCUG CUGAUGAGGCCGUUAGGCCGAA IAGACCUC 7521
1241 AGGUCUCC C AGGCCCCC 1490 GGGGGCCU CUGAUGAGGCCGUUAGGCCGAA IGAGACCU 7522
1242 GGUCUCCC A GGCCCCCU 1491 AGGGGGCC CUGAUGAGGCCGUUAGGCCGAA IGGAGACC 7523
1246 UCCCAGGC C CCCUUGCC 1492 GGCAAGGG CUGAUGAGGCCGUUAGGCCGAA ICCUGGGA 7524
1247 CCCAGGCC C CCUUGCCC 1493 GGGCAAGG CUGAUGAGGCCGUUAGGCCGAA IGCCUGGG 7525
1248 CCAGGCCC C CUUGCCCC 1494 GGGGCAAG CUGAUGAGGCCGUUAGGCCGAA IGGCCUGG 7526
1249 CAGGCCCC C UUGCCCCC 1495 GGGGGCAA CUGAUGAGGCCGUUAGGCCGAA IGGGCCUG 7527
1250 AGGCCCCC U UGCCCCCC 1496 GGGGGGCA CUGAUGAGGCCGUUAGGCCGAA IGGGGCCU 7528
1254 CCCCUUGC C CCCCGCCC 1497 GGGCGGGG CUGAUGAGGCCGUUAGGCCGAA ICAAGGGG 7529
1255 CCCUUGCC C CCCGCCCC 1498 GGGGCGGG CUGAUGAGGCCGUUAGGCCGAA IGCAAGGG 7530
1256 CCUUGCCC C CCGCCCCU 1499 AGGGGCGG CUGAUGAGGCCGUUAGGCCGAA IGGCAAGG 7531
1257 CUUGCCCC C CGCCCCUG 1500 CAGGGGCG CUGAUGAGGCCGUUAGGCCGAA IGGGCAAG 7532
1258 UUGCCCCC C GCCCCUGC 1501 GCAGGGGC CUGAUGAGGCCGUUAGGCCGAA IGGGGCAA 7533
1261 CCCCCCGC C CCUGCCUA 1502 UAGGCAGG CUGAUGAGGCCGUUAGGCCGAA ICGGGGGG 7534
1262 CCCCCGCC c CUGCCUAC 1503 GUAGGCAG CUGAUGAGGCCGUUAGGCCGAA IGCGGGGG 7535
1263 CCCCGCCC c UGCCUACC 1504 GGUAGGCA CUGAUGAGGCCGUUAGGCCGAA IGGCGGGG 7536
1264 CCCGCCCC u GCCUACCU 1505 AGGUAGGC CUGAUGAGGCCGUUAGGCCGAA IGGGCGGG 7537
1267 GCCCCUGC c UACCUCUC 1506 GAGAGGUA CUGAUGAGGCCGUUAGGCCGAA ICAGGGGC 7538
1268 CCCCUGCC u ACCUCUCC 1507 GGAGAGGU CUGAUGAGGCCGUUAGGCCGAA IGCAGGGG 7539
1271 CUGCCUAC c UCUCCUCU 1508 AGAGGAGA CUGAUGAGGCCGUUAGGCCGAA IUAGGCAG 7540
1272 UGCCUACC u CUCCUCUC 1509 GAGAGGAG CUGAUGAGGCCGUUAGGCCGAA IGUAGGCA 7541
1274 CCUACCUC u CCUCUCCC 1510 GGGAGAGG CUGAUGAGGCCGUUAGGCCGAA IAGGUAGG 7542
1276 UACCUCUC c UCUCCCCU 1511 AGGGGAGA CUGAUGAGGCCGUUAGGCCGAA lAGAGGUA 7543
1277 ACCUCUCC u CUCCCCUG 1512 CAGGGGAG CUGAUGAGGCCGUUAGGCCGAA IGAGAGGU 7544
1279 cucuccuc u CCCCUGGC 1513 GCCAGGGG CUGAUGAGGCCGUUAGGCCGAA IAGGAGAG 7545
1281 cuccucuc c CCUGGCCC 1514 GGGCCAGG CUGAUGAGGCCGUUAGGCCGAA IAGAGGAG 7546
1282 UCCUCUCC c CUGGCCCU 1515 AGGGCCAG CUGAUGAGGCCGUUAGGCCGAA IGAGAGGA 7547
1283 CCUCUCCC c UGGCCCUG 1516 CAGGGCCA CUGAUGAGGCCGUUAGGCCGAA IGGAGAGG 7548
1284 CUCUCCCC u GGCCCUGC 1517 GCAGGGCC CUGAUGAGGCCGUUAGGCCGAA IGGGAGAG 7549
1288 CCCCUGGC c CUGCCCAG 1518 CUGGGCAG CUGAUGAGGCCGUUAGGCCGAA ICCAGGGG 7550
1289 CCCUGGCC c UGCCCAGC 1519 GCUGGGCA CUGAUGAGGCCGUUAGGCCGAA IGCCAGGG 7551 1290 CCUGGCCC U GCCCAGCC 1520 GGCUGGGC CUGAUGAGGCCGUUAGGCCGAA IGGCCAGG 7552
1293 GGCCCUGC C CAGCCAGA 1521 UCUGGCUG CUGAUGAGGCCGUUAGGCCGAA ICAGGGCC 7553
1294 GCCCUGCC C AGCCAGAG 1522 CUCUGGCU CUGAUGAGGCCGUUAGGCCGAA IGCAGGGC 7554
1295 CCCUGCCC A GCCAGAGG 1523 CCUCUGGC CUGAUGAGGCCGUUAGGCCGAA IGGCAGGG 7555
1298 UGCCCAGC C AGAGGAGG 1524 CCUCCUCU CUGAUGAGGCCGUUAGGCCGAA ICUGGGCA 7556
1299 GCCCAGCC A GAGGAGGA 1525 UCCUCCUC CUGAUGAGGCCGUUAGGCCGAA IGCUGGGC 7557
1310 GGAGGAGC C CCCCCGAG 1526 CUCGGGGG CUGAUGAGGCCGUUAGGCCGAA ICUCCUCC 7558
1311 GAGGAGCC C CCCCGAGG 1527 CCUCGGGG CUGAUGAGGCCGUUAGGCCGAA IGCUCCUC 7559
1312 AGGAGCCC C CCCGAGGA 1528 UCCUCGGG CUGAUGAGGCCGUUAGGCCGAA IGGCUCCU 7560
1313 GGAGCCCC C CCGAGGAG 1529 CUCCUCGG CUGAUGAGGCCGUUAGGCCGAA IGGGCUCC 7561
1314 GAGCCCCC C CGAGGAGC 1530 GCUCCUCG CUGAUGAGGCCGUUAGGCCGAA IGGGGCUC 7562
1315 AGCCCCCC C GAGGAGCC 1531 GGCUCCUC CUGAUGAGGCCGUUAGGCCGAA IGGGGGCU 7563
1323 CGAGGAGC C ACCUGACU 1532 AGUCAGGU CUGAUGAGGCCGUUAGGCCGAA ICUCCUCG 7564
1324 GAGGAGCC A CCUGACUU 1533 AAGUCAGG CUGAUGAGGCCGUUAGGCCGAA IGCUCCUC 7565
1326 GGAGCCAC C UGACUUCU 1534 AGAAGUCA CUGAUGAGGCCGUUAGGCCGAA IUGGCUCC 7566
1327 GAGCCACC U GACUUCUG 1535 CAGAAGUC CUGAUGAGGCCGUUAGGCCGAA IGUGGCUC 7567
1331 CACCUGAC U UCUGCUGU 1536 ACAGCAGA CUGAUGAGGCCGUUAGGCCGAA IUCAGGUG 7568
1334 CUGACUUC U GCUGUCCC 1537 GGGACAGC CUGAUGAGGCCGUUAGGCCGAA IAAGUCAG 7569
1337 ACUUCUGC U GUCCCAAG 1538 CUUGGGAC CUGAUGAGGCCGUUAGGCCGAA ICAGAAGU 7570
1341 CUGCUGUC C CAAGUGCC 1539 GGCACUUG CUGAUGAGGCCGUUAGGCCGAA IACAGCAG 7571
1342 UGCUGUCC C AAGUGCCA 1540 UGGCACUU CUGAUGAGGCCGUUAGGCCGAA IGACAGCA 7572
1343 GCUGUCCC A AGUGCCAG 1541 CUGGCACU CUGAUGAGGCCGUUAGGCCGAA IGGACAGC 7573
1349 CCAAGUGC C AGUAUCAG 1542 CUGAUACU CUGAUGAGGCCGUUAGGCCGAA ICACUUGG 7574
1350 CAAGUGCC A GUAUCAGG 1543 CCUGAUAC CUGAUGAGGCCGUUAGGCCGAA IGCACUUG 7575
1356 CCAGUAUC A GGCCCCUG 1544 CAGGGGCC CUGAUGAGGCCGUUAGGCCGAA IAUACUGG 7576
1360 UAUCAGGC C CCUGAUAU 1545 AUAUCAGG CUGAUGAGGCCGUUAGGCCGAA ICCUGAUA 7577
1361 AUCAGGCC C CUGAUAUG 1546 CAUAUCAG CUGAUGAGGCCGUUAGGCCGAA IGCCUGAU 7578
1362 UCAGGCCC C UGAUAUGG 1547 CCAUAUCA CUGAUGAGGCCGUUAGGCCGAA IGGCCUGA 7579
1363 CAGGCCCC U GAUAUGGA 1548 UCCAUAUC CUGAUGAGGCCGUUAGGCCGAA IGGGCCUG 7580
1373 AUAUGGAC A CCCUGCAG 1549 CUGCAGGG CUGAUGAGGCCGUUAGGCCGAA IUCCAUAU 7581
1375 AUGGACAC C CUGCAGAU 1550 AUCUGCAG CUGAUGAGGCCGUUAGGCCGAA IUGUCCAU 7582
1376 UGGACACC C UGCAGAUA 1551 UAUCUGCA CUGAUGAGGCCGUUAGGCCGAA IGUGUCCA 7583
1377 GGACACCC U GCAGAUAC 1552 GUAUCUGC CUGAUGAGGCCGUUAGGCCGAA IGGUGUCC 7584
1380 CACCCUGC A GAUACAUG 1553 CAUGUAUC CUGAUGAGGCCGUUAGGCCGAA ICAGGGUG 7585
1386 GCAGAUAC A UGUCAUGG 1554 CCAUGACA CUGAUGAGGCCGUUAGGCCGAA IUAUCUGC 7586
1391 UACAUGUC A UGGAGUGC 1555 GCACUCCA CUGAUGAGGCCGUUAGGCCGAA IACAUGUA 7587
1400 UGGAGUGC A UUGAGUAG 1556 CUACUCAA CUGAUGAGGCCGUUAGGCCGAA ICACUCCA 7588
1412 AGUAGGGC C GGCCAGUG 1557 CACUGGCC CUGAUGAGGCCGUUAGGCCGAA ICCCUACU 7589
1416 GGGCCGGC C AGUGCAAG 1558 CUUGCACU CUGAUGAGGCCGUUAGGCCGAA ICCGGCCC 7590
1417 GGCCGGCC A GUGCAAGG 1559 CCUUGCAC CUGAUGAGGCCGUUAGGCCGAA IGCCGGCC 7591
1422 GCCAGUGC A AGGCCACU 1560 AGUGGCCU CUGAUGAGGCCGUUAGGCCGAA ICACUGGC 7592
1427 UGCAAGGC C ACUGCCUG 1561 CAGGCAGU CUGAUGAGGCCGUUAGGCCGAA ICCUUGCA 7593
1428 GCAAGGCC A CUGCCUGC 1562 GCAGGCAG CUGAUGAGGCCGUUAGGCCGAA IGCCUUGC 7594
1430 AAGGCCAC U GCCUGCCC 1563 GGGCAGGC CUGAUGAGGCCGUUAGGCCGAA IUGGCCUU 7595
1433 GCCACUGC C UGCCCGAG 1564 CUCGGGCA CUGAUGAGGCCGUUAGGCCGAA ICAGUGGC 7596
1434 CCACUGCC U GCCCGAGG 1565 CCUCGGGC CUGAUGAGGCCGUUAGGCCGAA IGCAGUGG 7597
1437 CUGCCUGC C CGAGGACG 1566 CGUCCUCG CUGAUGAGGCCGUUAGGCCGAA ICAGGCAG 7598
1438 UGCCUGCC C GAGGACGU 1567 ACGUCCUC CUGAUGAGGCCGUUAGGCCGAA IGCAGGCA 7599
1449 GGACGUGC C CGGGACCG 1568 CGGUCCCG CUGAUGAGGCCGUUAGGCCGAA ICACGUCC 7600
1450 GACGUGCC C GGGACCGU 1569 ACGGUCCC CUGAUGAGGCCGUUAGGCCGAA IGCACGUC 7601
1456 CCCGGGAC C GUGCAGUC 1570 GACUGCAC CUGAUGAGGCCGUUAGGCCGAA IUCCCGGG 7602 1461 GACCGUGC A GUCUGCGC 1571 GCGCAGAC CUGAUGAGGCCGUUAGGCCGAA ICACGGUC 7603
1465 GUGCAGUC U GCGCUUUC 1572 GAAAGCGC CUGAUGAGGCCGUUAGGCCGAA IACUGCAC 7604
1470 GUCUGCGC U UUCCUCUC 1573 GAGAGGAA CUGAUGAGGCCGUUAGGCCGAA ICGCAGAC 7605
1474 GCGCUUUC C UCUCCCGC 1574 GCGGGAGA CUGAUGAGGCCGUUAGGCCGAA IAAAGCGC 7606
1475 CGCUUUCC U CUCCCGCC 1575 GGCGGGAG CUGAUGAGGCCGUUAGGCCGAA IGAAAGCG 7607
1477 CUUUCCUC U CCCGCCUG 1576 CAGGCGGG CUGAUGAGGCCGUUAGGCCGAA IAGGAAAG 7608
1479 UUCCUCUC C CGCCUGCC 1577 GGCAGGCG CUGAUGAGGCCGUUAGGCCGAA lAGAGGAA 7609
1480 UCCUCUCC C GCCUGCCU 1578 AGGCAGGC CUGAUGAGGCCGUUAGGCCGAA IGAGAGGA 7610
1483 UCUCCCGC C UGCCUAGC 1579 GCUAGGCA CUGAUGAGGCCGUUAGGCCGAA ICGGGAGA 7611
1484 CUCCCGCC U GCCUAGCC 1580 GGCUAGGC CUGAUGAGGCCGUUAGGCCGAA IGCGGGAG 7612
1487 CCGCCUGC C UAGCCCAG 1581 CUGGGCUA CUGAUGAGGCCGUUAGGCCGAA ICAGGCGG 7613
1488 CGCCUGCC U AGCCCAGG 1582 CCUGGGCU CUGAUGAGGCCGUUAGGCCGAA IGCAGGCG 7614
1492 UGCCUAGC C CAGGAUGA 1583 UCAUCCUG CUGAUGAGGCCGUUAGGCCGAA ICUAGGCA 7615
1493 GCCUAGCC C AGGAUGAA 1584 UUCAUCCU CUGAUGAGGCCGUUAGGCCGAA IGCUAGGC 7616
1494 CCUAGCCC A GGAUGAAG 1585 CUUCAUCC CUGAUGAGGCCGUUAGGCCGAA IGGCUAGG 7617
1506 UGAAGGGC U GGGUGGCC 1586 GGCCACCC CUGAUGAGGCCGUUAGGCCGAA ICCCUUCA 7618
1514 UGGGUGGC C ACAACUGG 1587 CCAGUUGU CUGAUGAGGCCGUUAGGCCGAA ICCACCCA 7619
1515 GGGUGGCC A CAACUGGG 1588 CCCAGUUG CUGAUGAGGCCGUUAGGCCGAA IGCCACCC 7620
1517 GUGGCCAC A ACUGGGAU 1589 AUCCCAGU CUGAUGAGGCCGUUAGGCCGAA IUGGCCAC 7621
1520 GCCACAAC U GGGAUGCC 1590 GGCAUCCC CUGAUGAGGCCGUUAGGCCGAA IUUGUGGC 7622
1528 UGGGAUGC C ACCUGGAG 1591 CUCCAGGU CUGAUGAGGCCGUUAGGCCGAA ICAUCCCA 7623
1529 GGGAUGCC A CCUGGAGC 1592 GCUCCAGG CUGAUGAGGCCGUUAGGCCGAA IGCAUCCC 7624
1531 GAUGCCAC C UGGAGCCC 1593 GGGCUCCA CUGAUGAGGCCGUUAGGCCGAA IUGGCAUC 7625
1532 AUGCCACC U GGAGCCCC 1594 GGGGCUCC CUGAUGAGGCCGUUAGGCCGAA IGUGGCAU 7626
1538 CCUGGAGC C CCACCCAG 1595 CUGGGUGG CUGAUGAGGCCGUUAGGCCGAA ICUCCAGG 7627
1539 CUGGAGCC C CACCCAGG 1596 CCUGGGUG CUGAUGAGGCCGUUAGGCCGAA IGCUCCAG 7628
1540 UGGAGCCC C ACCCAGGA 1597 UCCUGGGU CUGAUGAGGCCGUUAGGCCGAA IGGCUCCA 7629
1541 GGAGCCCC A CCCAGGAG 1598 CUCCUGGG CUGAUGAGGCCGUUAGGCCGAA IGGGCUCC 7630
1543 AGCCCCAC C CAGGAGCU 1599 AGCUCCUG CUGAUGAGGCCGUUAGGCCGAA IUGGGGCU 7631
1544 GCCCCACC C AGGAGCUG 1600 CAGCUCCU CUGAUGAGGCCGUUAGGCCGAA IGUGGGGC 7632
1545 CCCCACCC A GGAGCUGG 1601 CCAGCUCC CUGAUGAGGCCGUUAGGCCGAA IGGUGGGG 7633
1551 CCAGGAGC u GGCCGCGG 1602 CCGCGGCC CUGAUGAGGCCGUUAGGCCGAA ICUCCUGG 7634
1555 GAGCUGGC c GCGGCACC 1603 GGUGCCGC CUGAUGAGGCCGUUAGGCCGAA ICCAGCUC 7635
1561 GCCGCGGC A CCUUACGC 1604 GCGUAAGG CUGAUGAGGCCGUUAGGCCGAA ICCGCGGC 7636
1563 CGCGGCAC C UUACGCUU 1605 AAGCGUAA CUGAUGAGGCCGUUAGGCCGAA IUGCCGCG 7637
1564 GCGGCACC U UACGCUUC 1606 GAAGCGUA CUGAUGAGGCCGUUAGGCCGAA IGUGCCGC 7638
1570 CCUUACGC U UCAGCUGU 1607 ACAGCUGA CUGAUGAGGCCGUUAGGCCGAA ICGUAAGG 7639
1573 UACGCUUC A GCUGUUGA 1608 UCAACAGC CUGAUGAGGCCGUUAGGCCGAA IAAGCGUA 7640
1576 GCUUCAGC U GUUGAUCC 1609 GGAUCAAC CUGAUGAGGCCGUUAGGCCGAA ICUGAAGC 7641
1584 UGUUGAUC C GCUGGUCC 1610 GGACCAGC CUGAUGAGGCCGUUAGGCCGAA IAUCAACA 7642
1587 UGAUCCGC U GGUCCCCU 1611 AGGGGACC CUGAUGAGGCCGUUAGGCCGAA ICGGAUCA 7643
1592 CGCUGGUC C CCUCUUUU 1612 AAAAGAGG CUGAUGAGGCCGUUAGGCCGAA IACCAGCG 7644
1593 GCUGGUCC C CUCUUUUG 1613 CAAAAGAG CUGAUGAGGCCGUUAGGCCGAA IGACCAGC 7645
1594 CUGGUCCC C UCUUUUGG 1614 CCAAAAGA CUGAUGAGGCCGUUAGGCCGAA IGGACCAG 7646
1595 UGGUCCCC U CUUUUGGG 1615 CCCAAAAG CUGAUGAGGCCGUUAGGCCGAA IGGGACCA 7647
1597 GUCCCCUC U UUUGGGGU 1616 ACCCCAAA CUGAUGAGGCCGUUAGGCCGAA IAGGGGAC 7648
1615 GAUGCGGC C CCGAUCAG 1617 CUGAUCGG CUGAUGAGGCCGUUAGGCCGAA ICCGCAUC 7649
1616 AUGCGGCC C CGAUCAGG 1618 CCUGAUCG CUGAUGAGGCCGUUAGGCCGAA IGCCGCAU 7650
1617 UGCGGCCC C GAUCAGGC 1619 GCCUGAUC CUGAUGAGGCCGUUAGGCCGAA IGGCCGCA 7651
1622 CCCCGAUC A GGCCUGAC 1620 GUCAGGCC CUGAUGAGGCCGUUAGGCCGAA IAUCGGGG 7652
1626 GAUCAGGC C UGACUCGC 1621 GCGAGUCA CUGAUGAGGCCGUUAGGCCGAA ICCUGAUC 7653 1627 AUCAGGCC U GACUCGCU 1622 AGCGAGUC CUGAUGAGGCCGUUAGGCCGAA IGCCUGAU 7654
1631 GGCCUGAC U CGCUGCUC 1623 GAGCAGCG CUGAUGAGGCCGUUAGGCCGAA IUCAGGCC 7655
1635 UGACUCGC U GCUCUUUU 1624 AAAAGAGC CUGAUGAGGCCGUUAGGCCGAA ICGAGUCA 7656
1638 CUCGCUGC U CUUUUUGU 1625 ACAAAAAG CUGAUGAGGCCGUUAGGCCGAA ICAGCGAG 7657
1640 CGCUGCUC U UUUUGUUC 1626 GAACAAAA CUGAUGAGGCCGUUAGGCCGAA IAGCAGCG 7658
1649 UUUUGUUC C CUUCUGUC 1627 GACAGAAG CUGAUGAGGCCGUUAGGCCGAA IAACAAAA 7659
1650 UUUGUUCC C UUCUGUCU 1628 AGACAGAA CUGAUGAGGCCGUUAGGCCGAA IGAACAAA 7660
1651 UUGUUCCC U UCUGUCUG 1629 CAGACAGA CUGAUGAGGCCGUUAGGCCGAA IGGAACAA 7661
1654 UUCCCUUC U GUCUGCUC 1630 GAGCAGAC CUGAUGAGGCCGUUAGGCCGAA IAAGGGAA 7662
1658 CUUCUGUC U GCUCGAAC 1631 GUUCGAGC CUGAUGAGGCCGUUAGGCCGAA IACAGAAG 7663
1661 CUGUCUGC U CGAACCAC 1632 GUGGUUCG CUGAUGAGGCCGUUAGGCCGAA ICAGACAG 7664
1667 GCUCGAAC C ACUUGCCU 1633 AGGCAAGU CUGAUGAGGCCGUUAGGCCGAA IUUCGAGC 7665
1668 CUCGAACC A CUUGCCUC 1634 GAGGCAAG CUGAUGAGGCCGUUAGGCCGAA IGUUCGAG 7666
1670 CGAACCAC U UGCCUCGG 1635 CCGAGGCA CUGAUGAGGCCGUUAGGCCGAA IUGGUUCG 7667
1674 CCACUUGC C UCGGGCUA 1636 UAGCCCGA CUGAUGAGGCCGUUAGGCCGAA ICAAGUGG 7668
1675 CACUUGCC U CGGGCUAA 1637 UUAGCCCG CUGAUGAGGCCGUUAGGCCGAA IGCAAGUG 7669
1681 CCUCGGGC U AAUCCCUC 1638 GAGGGAUU CUGAUGAGGCCGUUAGGCCGAA ICCCGAGG 7670
1686 GGCUAAUC C CUCCCUCU 1639 AGAGGGAG CUGAUGAGGCCGUUAGGCCGAA IAUUAGCC 7671
1687 GCUAAUCC c UCCCUCUU 1640 AAGAGGGA CUGAUGAGGCCGUUAGGCCGAA IGAUUAGC 7672
1688 CUAAUCCC u CCCUCUUC 1641 GAAGAGGG CUGAUGAGGCCGUUAGGCCGAA IGGAUUAG 7673
1690 AAUCCCUC c cucuuccu 1642 AGGAAGAG CUGAUGAGGCCGUUAGGCCGAA IAGGGAUU 7674
1691 AUCCCUCC c ucuuccuc 1643 GAGGAAGA CUGAUGAGGCCGUUAGGCCGAA IGAGGGAU 7675
1692 UCCCUCCC u cuuccucc 1644 GGAGGAAG CUGAUGAGGCCGUUAGGCCGAA IGGAGGGA 7676
1694 CCUCCCUC u UCCUCCAC 1645 GUGGAGGA CUGAUGAGGCCGUUAGGCCGAA IAGGGAGG 7677
1697 cccucuuc c UCCACCCG 1646 CGGGUGGA CUGAUGAGGCCGUUAGGCCGAA IAAGAGGG 7678
1698 CCUCUUCC u CCACCCGG 1647 CCGGGUGG CUGAUGAGGCCGUUAGGCCGAA IGAAGAGG 7679
1700 ucuuccuc c ACCCGGCA 1648 UGCCGGGU CUGAUGAGGCCGUUAGGCCGAA lAGGAAGA 7680
1701 cuuccucc A CCCGGCAC 1649 GUGCCGGG CUGAUGAGGCCGUUAGGCCGAA IGAGGAAG 7681
1703 UCCUCCAC C CGGCACUG 1650 CAGUGCCG CUGAUGAGGCCGUUAGGCCGAA IUGGAGGA 7682
1704 CCUCCACC c GGCACUGG 1651 CCAGUGCC CUGAUGAGGCCGUUAGGCCGAA IGUGGAGG 7683
1708 CACCCGGC A CUGGGGAA 1652 UUCCCCAG CUGAUGAGGCCGUUAGGCCGAA ICCGGGUG 7684
1710 CCCGGCAC U GGGGAAGU 1653 ACUUCCCC CUGAUGAGGCCGUUAGGCCGAA IUGCCGGG 7685
1720 GGGAAGUC A AGAAUGGG 1654 CCCAUUCU CUGAUGAGGCCGUUAGGCCGAA IACUUCCC 7686
1731 AAUGGGGC C UGGGGCUC 1655 GAGCCCCA CUGAUGAGGCCGUUAGGCCGAA ICCCCAUU 7687
1732 AUGGGGCC U GGGGCUCU 1656 AGAGCCCC CUGAUGAGGCCGUUAGGCCGAA IGCCCCAU 7688
1738 CCUGGGGC U CUCAGGGA 1657 UCCCUGAG CUGAUGAGGCCGUUAGGCCGAA ICCCCAGG 7689
1740 UGGGGCUC U CAGGGAGA 1658 UCUCCCUG CUGAUGAGGCCGUUAGGCCGAA IAGCCCCA 7690
1742 GGGCUCUC A GGGAGAAC 1659 GUUCUCCC CUGAUGAGGCCGUUAGGCCGAA IAGAGCCC 7691
1751 GGGAGAAC U GCUUCCCC 1660 GGGGAAGC CUGAUGAGGCCGUUAGGCCGAA IUUCUCCC 7692
1754 AGAACUGC U UCCCCUGG 1661 CCAGGGGA CUGAUGAGGCCGUUAGGCCGAA ICAGUUCU 7693
1757 ACUGCUUC C CCUGGCAG 1662 CUGCCAGG CUGAUGAGGCCGUUAGGCCGAA IAAGCAGU 7694
1758 CUGCUUCC C CUGGCAGA 1663 UCUGCCAG CUGAUGAGGCCGUUAGGCCGAA IGAAGCAG 7695
1759 UGCUUCCC C UGGCAGAG 1664 CUCUGCCA CUGAUGAGGCCGUUAGGCCGAA IGGAAGCA 7696
1760 GCUUCCCC U GGCAGAGC 1665 GCUCUGCC CUGAUGAGGCCGUUAGGCCGAA IGGGAAGC 7697
1764 CCCCUGGC A GAGCUGGG 1666 CCCAGCUC CUGAUGAGGCCGUUAGGCCGAA ICCAGGGG 7698
1769 GGCAGAGC U GGGUGGCA 1667 UGCCACCC CUGAUGAGGCCGUUAGGCCGAA ICUCUGCC 7699
1777 UGGGUGGC A GCUCUUCC 1668 GGAAGAGC CUGAUGAGGCCGUUAGGCCGAA ICCACCCA 7700
1780 GUGGCAGC U CUUCCUCC 1669 GGAGGAAG CUGAUGAGGCCGUUAGGCCGAA ICUGCCAC 7701
1782 GGCAGCUC U UCCUCCCA 1670 UGGGAGGA CUGAUGAGGCCGUUAGGCCGAA IAGCUGCC 7702
1785 AGCUCUUC C UCCCACCG 1671 CGGUGGGA CUGAUGAGGCCGUUAGGCCGAA IAAGAGCU 7703
1786 GCUCUUCC U CCCACCGG 1672 CCGGUGGG CUGAUGAGGCCGUUAGGCCGAA IGAAGAGC 7704 1788 UCUUCCUC C CACCGGAC 1673 GUCCGGUG CUGAUGAGGCCGUUAGGCCGAA lAGGAAGA 7705
1789 CUUCCUCC C ACCGGACA 1674 UGUCCGGU CUGAUGAGGCCGUUAGGCCGAA IGAGGAAG 7706
1790 UUCCUCCC A CCGGACAC 1675 GUGUCCGG CUGAUGAGGCCGUUAGGCCGAA IGGAGGAA 7707
1792 CCUCCCAC C GGACACCG 1676 CGGUGUCC CUGAUGAGGCCGUUAGGCCGAA IUGGGAGG 7708
1797 CACCGGAC A CCGACCCG 1677 CGGGUCGG CUGAUGAGGCCGUUAGGCCGAA IUCCGGUG 7709
1799 CCGGACAC C GACCCGCC 1678 GGCGGGUC CUGAUGAGGCCGUUAGGCCGAA IUGUCCGG 7710
1803 ACACCGAC C CGCCCGCC 1679 GGCGGGCG CUGAUGAGGCCGUUAGGCCGAA IUCGGUGU 7711
1804 CACCGACC C GCCCGCCG 1680 CGGCGGGC CUGAUGAGGCCGUUAGGCCGAA IGUCGGUG 7712
1807 CGACCCGC C CGCCGCUG 1681 CAGCGGCG CUGAUGAGGCCGUUAGGCCGAA ICGGGUCG 7713
1808 GACCCGCC C GCCGCUGU 1682 ACAGCGGC CUGAUGAGGCCGUUAGGCCGAA IGCGGGUC 7714
1811 CCGCCCGC C GCUGUGCC 1683 GGCACAGC CUGAUGAGGCCGUUAGGCCGAA ICGGGCGG 7715
1814 CCCGCCGC U GUGCCCUG 1684 CAGGGCAC CUGAUGAGGCCGUUAGGCCGAA ICGGCGGG 7716
1819 CGCUGUGC c CUGGGAGU 1685 ACUCCCAG CUGAUGAGGCCGUUAGGCCGAA ICACAGCG 7717
1820 GCUGUGCC c UGGGAGUG 1686 CACUCCCA CUGAUGAGGCCGUUAGGCCGAA IGCACAGC 7718
1821 CUGUGCCC u GGGAGUGC 1687 GCACUCCC CUGAUGAGGCCGUUAGGCCGAA IGGCACAG 7719
1830 GGGAGUGC u GCCCUCUU 1688 AAGAGGGC CUGAUGAGGCCGUUAGGCCGAA ICACUCCC 7720
1833 AGUGCUGC c CUCUUACC 1689 GGUAAGAG CUGAUGAGGCCGUUAGGCCGAA ICAGCACU 7721
1834 GUGCUGCC c UCUUACCA 1690 UGGUAAGA CUGAUGAGGCCGUUAGGCCGAA IGCAGCAC 7722
1835 UGCUGCCC u CUUACCAU 1691 AUGGUAAG CUGAUGAGGCCGUUAGGCCGAA IGGCAGCA 7723
1837 CUGCCCUC u UACCAUGC 1692 GCAUGGUA CUGAUGAGGCCGUUAGGCCGAA IAGGGCAG 7724
1841 CCUCUUAC c AUGCACAC 1693 GUGUGCAU CUGAUGAGGCCGUUAGGCCGAA IUAAGAGG 7725
1842 CUCUUACC A UGCACACG 1694 CGUGUGCA CUGAUGAGGCCGUUAGGCCGAA IGUAAGAG 7726
1846 UACCAUGC A CACGGGUG 1695 CACCCGUG CUGAUGAGGCCGUUAGGCCGAA ICAUGGUA 7727
1848 CCAUGCAC A CGGGUGCU 1696 AGCACCCG CUGAUGAGGCCGUUAGGCCGAA IUGCAUGG 7728
1856 ACGGGUGC U CUCCUUUU 1697 AAAAGGAG CUGAUGAGGCCGUUAGGCCGAA ICACCCGU 7729
1858 GGGUGCUC U CCUUUUGG 1698 CCAAAAGG CUGAUGAGGCCGUUAGGCCGAA IAGCACCC 7730
1860 GUGCUCUC C UUUUGGGC 1699 GCCCAAAA CUGAUGAGGCCGUUAGGCCGAA IAGAGCAC 7731
1861 UGCUCUCC U UUUGGGCU 1700 AGCCCAAA CUGAUGAGGCCGUUAGGCCGAA IGAGAGCA 7732
1869 UUUUGGGC u GCAUGCUA 1701 UAGCAUGC CUGAUGAGGCCGUUAGGCCGAA ICCCAAAA 7733
1872 UGGGCUGC A UGCUAUUC 1702 GAAUAGCA CUGAUGAGGCCGUUAGGCCGAA ICAGCCCA 7734
1876 CUGCAUGC U AUUCCAUU 1703 AAUGGAAU CUGAUGAGGCCGUUAGGCCGAA ICAUGCAG 7735
1881 UGCUAUUC C AUUUUGCA 1704 UGCAAAAU CUGAUGAGGCCGUUAGGCCGAA IAAUAGCA 7736
1882 GCUAUUCC A UUUUGCAG 1705 CUGCAAAA CUGAUGAGGCCGUUAGGCCGAA IGAAUAGC 7737
1889 CAUUUUGC A GCCAGACC 1706 GGUCUGGC CUGAUGAGGCCGUUAGGCCGAA ICAAAAUG 7738
1892 UUUGCAGC C AGACCGAU 1707 AUCGGUCU CUGAUGAGGCCGUUAGGCCGAA ICUGCAAA 7739
1893 UUGCAGCC A GACCGAUG 1708 CAUCGGUC CUGAUGAGGCCGUUAGGCCGAA IGCUGCAA 7740
1897 AGCCAGAC C GAUGUGUA 1709 UACACAUC CUGAUGAGGCCGUUAGGCCGAA IUCUGGCU 7741
1912 UAUUUAAC C AGUCACUA 1710 UAGUGACU CUGAUGAGGCCGUUAGGCCGAA IUUAAAUA 7742
1913 AUUUAACC A GUCACUAU 1711 AUAGUGAC CUGAUGAGGCCGUUAGGCCGAA IGUUAAAU 7743
1917 AACCAGUC A CUAUUGAU 1712 AUCAAUAG CUGAUGAGGCCGUUAGGCCGAA IACUGGUU 7744
1919 CCAGUCAC U AUUGAUGG 1713 CCAUCAAU CUGAUGAGGCCGUUAGGCCGAA IUGACUGG 7745
1930 UGAUGGAC A UUUGGGUU 1714 AACCCAAA CUGAUGAGGCCGUUAGGCCGAA IUCCAUCA 7746
1944 GUUGUUUC C CAUCUUUU 1715 AAAAGAUG CUGAUGAGGCCGUUAGGCCGAA IAAACAAC 7747
1945 UUGUUUCC C AUCUUUUU 1716 AAAAAGAU CUGAUGAGGCCGUUAGGCCGAA IGAAACAA 7748
1946 UGUUUCCC A UCUUUUUG 1717 CAAAAAGA CUGAUGAGGCCGUUAGGCCGAA IGGAAACA 7749
1949 UUCCCAUC U UUUUGUUA 1718 UAACAAAA CUGAUGAGGCCGUUAGGCCGAA IAUGGGAA 7750
1959 UUUGUUAC C AUAAAUAA 1719 UUAUUUAU CUGAUGAGGCCGUUAGGCCGAA lUAACAAA 7751
1960 UUGUUACC A UAAAUAAU 1720 AUUAUUUA CUGAUGAGGCCGUUAGGCCGAA IGUAACAA 7752
1972 AUAAUGGC A UAGUAAAA 1721 UUUUACUA CUGAUGAGGCCGUUAGGCCGAA ICCAUUAU 7753
Input Sequence = NM_003639. Cut Site = CH/ . Arm Length = 8. Core Sequence = CUGAUGAG GCCGUUAGGC CGAA
NM_003639 (Homo sapiens inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma (IKBKG) , mRNA. ; 1994 bp)
Underlined region can be any X sequence or linker, as described herein. "I" stands for Inosine.
Table X: Human IKK-gamma Zinzyme and Substrate Sequence
Pos Substrate Seq Zinzyme Seq ID ID
13 CGAGCAUG G CCCUUGUG 1722 CACAAGGG GCCGAAAGGCGAGUGAGGUCU CAUGCUCG 7754
19 UGGCCCUU G UGAUCCAG 1723 CUGGAUCA GCCGAAAGGCGAGUGAGGUCU AAGGGCCA 7755
28 UGAUCCAG G UGGGGAAA 1724 UUUCCCCA GCCGAAAGGCGAGUGAGGUCU CUGGAUCA 7756
42 AAACUAAG G CCCAGAGA 1725 UCUCUGGG GCCGAAAGGCGAGUGAGGUCU CUUAGUUU 7757
52 CCAGAGAA G UGAGGACC 1726 GGUCCUCA GCCGAAAGGCGAGUGAGGUCU UUCUCUGG 7758
63 AGGACCCC G CAGACUAU 1727 AUAGUCUG GCCGAAAGGCGAGUGAGGUCU GGGGUCCU 7759
80 CAAUCCCA G UCUCUUCC 1728 GGAAGAGA GCCGAAAGGCGAGUGAGGUCU UGGGAUUG 7760
100 CACUCCCU G UGAAGCUC 1729 GAGCUUCA GCCGAAAGGCGAGUGAGGUCU AGGGAGUG 7761
105 CCUGUGAA G CUCUCCAG 1730 CUGGAGAG GCCGAAAGGCGAGUGAGGUCU UUCACAGG 7762
113 GCUCUCCA G CAUCAUCG 1731 CGAUGAUG GCCGAAAGGCGAGUGAGGUCU UGGAGAGC 7763
124 UCAUCGAG G UCCCAUCA 1732 UGAUGGGA GCCGAAAGGCGAGUGAGGUCU CUCGAUGA 7764
133 UCCCAUCA G CCCUUGCC 1733 GGCAAGGG GCCGAAAGGCGAGUGAGGUCU UGAUGGGA 7765
139 CAGCCCUU G CCCUGUUG 1734 CAACAGGG GCCGAAAGGCGAGUGAGGUCU AAGGGCUG 7766
144 CUUGCCCU G UUGGAUGA 1735 UCAUCCAA GCCGAAAGGCGAGUGAGGUCU AGGGCAAG 7767
157 AUGAAUAG G CACCUCUG 1736 CAGAGGUG GCCGAAAGGCGAGUGAGGUCU CUAUUCAU 7768
171 CUGGAAGA G CCAACUGU 1737 ACAGUUGG GCCGAAAGGCGAGUGAGGUCU UCUUCCAG 7769
178 AGCCAACU G UGUGAGAU 1738 AUCUCACA GCCGAAAGGCGAGUGAGGUCU AGUUGGCU 7770
180 CCAACUGU G UGAGAUGG 1739 CCAUCUCA GCCGAAAGGCGAGUGAGGUCU ACAGUUGG 7771
188 GUGAGAUG G UGCAGCCC 1740 GGGCUGCA GCCGAAAGGCGAGUGAGGUCU CAUCUCAC 7772
190 GAGAUGGU G CAGCCCAG 1741 CUGGGCUG GCCGAAAGGCGAGUGAGGUCU ACCAUCUC 7773
193 AUGGUGCA G CCCAGUGG 1742 CCACUGGG GCCGAAAGGCGAGUGAGGUCU UGCACCAU 7774
198 GCAGCCCA G UGGUGGCC 1743 GGCCACCA GCCGAAAGGCGAGUGAGGUCU UGGGCUGC 7775
201 GCCCAGUG G UGGCCCGG 1744 CCGGGCCA GCCGAAAGGCGAGUGAGGUCU CACUGGGC 7776
204 CAGUGGUG G CCCGGCAG 1745 CUGCCGGG GCCGAAAGGCGAGUGAGGUCU CACCACUG 7777
209 GUGGCCCG G CAGCAGAU 1746 AUCUGCUG GCCGAAAGGCGAGUGAGGUCU CGGGCCAC 7778
212 GCCCGGCA G CAGAUCAG 1747 CUGAUCUG GCCGAAAGGCGAGUGAGGUCU UGCCGGGC 7779
224 AUCAGGAC G UACUGGGC 1748 GCCCAGUA GCCGAAAGGCGAGUGAGGUCU GUCCUGAU 7780
231 CGUACUGG G CGAAGAGU 1749 ACUCUUCG GCCGAAAGGCGAGUGAGGUCU CCAGUACG 7781
238 GGCGAAGA G UCUCCUCU 1750 AGAGGAGA GCCGAAAGGCGAGUGAGGUCU UCUUCGCC 7782
253 CUGGGGAA G CCAGCCAU 1751 AUGGCUGG GCCGAAAGGCGAGUGAGGUCU UUCCCCAG 7783
257 GGAAGCCA G CCAUGCUG 1752 CAGCAUGG GCCGAAAGGCGAGUGAGGUCU UGGCUUCC 7784
262 CCAGCCAU G CUGCACCU 1753 AGGUGCAG GCCGAAAGGCGAGUGAGGUCU AUGGCUGG 7785
265 GCCAUGCU G CACCUGCC 1754 GGCAGGUG GCCGAAAGGCGAGUGAGGUCU AGCAUGGC 7786
271 CUGCACCU G CCUUCAGA 1755 UCUGAAGG GCCGAAAGGCGAGUGAGGUCU AGGUGCAG 7787
285 AGAACAGG G CGCUCCUG 1756 CAGGAGCG GCCGAAAGGCGAGUGAGGUCU CCUGUUCU 7788
287 AACAGGGC G CUCCUGAG 1757 CUCAGGAG GCCGAAAGGCGAGUGAGGUCU GCCCUGUU 7789
304 ACCCUCCA G CGCUGCCU 1758 AGGCAGCG GCCGAAAGGCGAGUGAGGUCU UGGAGGGU 7790
306 CCUCCAGC G CUGCCUGG 1759 CCAGGCAG GCCGAAAGGCGAGUGAGGUCU GCUGGAGG 7791
309 CCAGCGCU G CCUGGAGG 1760 CCUCCAGG GCCGAAAGGCGAGUGAGGUCU AGCGCUGG 7792
328 AAUCAAGA G CUCCGAGA 1761 UCUCGGAG GCCGAAAGGCGAGUGAGGUCU UCUUGAUU 7793
338 UCCGAGAU G CCAUCCGG 1762 CCGGAUGG GCCGAAAGGCGAGUGAGGUCU AUCUCGGA 7794
346 GCCAUCCG G CAGAGCAA 1763 UUGCUCUG GCCGAAAGGCGAGUGAGGUCU CGGAUGGC 7795
351 CCGGCAGA G CAACCAGA 1764 UCUGGUUG GCCGAAAGGCGAGUGAGGUCU UCUGCCGG 7796
364 CAGAUUCU G CGGGAGCG 1765 CGCUCCCG GCCGAAAGGCGAGUGAGGUCU AGAAUCUG 7797
370 CUGCGGGA G CGCUGCGA 1766 UCGCAGCG GCCGAAAGGCGAGUGAGGUCU UCCCGCAG 7798
372 GCGGGAGC G CUGCGAGG 1767 CCUCGCAG GCCGAAAGGCGAGUGAGGUCU GCUCCCGC 7799
375 GGAGCGCU G CGAGGAGC 1768 GCUCCUCG GCCGAAAGGCGAGUGAGGUCU AGCGCUCC 7800 382 UGCGAGGA G CUUCUGCA 1769 UGCAGAAG GCCGAAAGGCGAGUGAGGUCU UCCUCGCA 7801
388 GAGCUUCU G CAUUUCCA 177U UGGAAAUG GCCGAAAGGCGAGUGAGGUCU AGAAGCUC 7802
398 AUUUCCAA G CCAGCCAG 1771 CUGGCUGG GCCGAAAGGCGAGUGAGGUCU UUGGAAAU 7803
402 CCAAGCCA G CCAGAGGG 1772 CCCUCUGG GCCGAAAGGCGAGUGAGGUCU UGGCUUGG 7804
421 GAGAAGGA G UUCCUCAU 1773 AUGAGGAA GCCGAAAGGCGAGUGAGGUCU UCCUUCUC 7805
430 UUCCUCAU G UGCAAGUU 1774 AACUUGCA GCCGAAAGGCGAGUGAGGUCU AUGAGGAA 7806
432 CCUCAUGU G CAAGUUCC 1775 GGAACUUG GCCGAAAGGCGAGUGAGGUCU ACAUGAGG 7807
436 AUGUGCAA G UUCCAGGA 1776 UCCUGGAA GCCGAAAGGCGAGUGAGGUCU UUGCACAU 7808
446 UCCAGGAG G CCAGGAAA 1777 UUUCCUGG GCCGAAAGGCGAGUGAGGUCU CUCCUGGA 7809
458 GGAAACUG G UGGAGAGA 1778 UCUCUCCA GCCGAAAGGCGAGUGAGGUCU CAGUUUCC 7810
471 GAGACUCG G CCUGGAGA 1779 UCUCCAGG GCCGAAAGGCGAGUGAGGUCU CGAGUCUC 7811
481 CUGGAGAA G CUCGAUCU 1780 AGAUCGAG GCCGAAAGGCGAGUGAGGUCU UUCUCCAG 7812
496 CUGAAGAG G CAGAAGGA 1781 UCCUUCUG GCCGAAAGGCGAGUGAGGUCU CUCUUCAG 7813
505 CAGAAGGA G CAGGCUCU 1782 AGAGCCUG GCCGAAAGGCGAGUGAGGUCU UCCUUCUG 7814
509 AGGAGCAG G CUCUGCGG 1783 CCGCAGAG GCCGAAAGGCGAGUGAGGUCU CUGCUCCU 7815
514 CAGGCUCU G CGGGAGGU 1784 ACCUCCCG GCCGAAAGGCGAGUGAGGUCU AGAGCCUG 7816
521 UGCGGGAG G UGGAGCAC 1785 GUGCUCCA GCCGAAAGGCGAGUGAGGUCU CUCCCGCA 7817
526 GAGGUGGA G CACCUGAA 1786 UUCAGGUG GCCGAAAGGCGAGUGAGGUCU UCCACCUC 7818
540 GAAGAGAU G CCAGCAGC 1787 GCUGCUGG GCCGAAAGGCGAGUGAGGUCU AUCUCUUC 7819
544 AGAUGCCA G CAGCAGAU 1788 AUCUGCUG GCCGAAAGGCGAGUGAGGUCU UGGCAUCU 7820
547 UGCCAGCA G CAGAUGGC 1789 GCCAUCUG GCCGAAAGGCGAGUGAGGUCU UGCUGGCA 7821
554 AGCAGAUG G CUGAGGAC 1790 GUCCUCAG GCCGAAAGGCGAGUGAGGUCU CAUCUGCU 7822
566 AGGACAAG G CCUCUGUG 1791 CACAGAGG GCCGAAAGGCGAGUGAGGUCU CUUGUCCU 7823
572 AGGCCUCU G UGAAAGCC 1792 GGCUUUCA GCCGAAAGGCGAGUGAGGUCU AGAGGCCU 7824
578 CUGUGAAA G CCCAGGUG 1793 CACCUGGG GCCGAAAGGCGAGUGAGGUCU UUUCACAG 7825
584 AAGCCCAG G UGACGUCC 1794 GGACGUCA GCCGAAAGGCGAGUGAGGUCU CUGGGCUU 7826
589 CAGGUGAC G UCCUUGCU 1795 AGCAAGGA GCCGAAAGGCGAGUGAGGUCU GUCACCUG 7827
595 ACGUCCUU G CUCGGGGA 1796 UCCCCGAG GCCGAAAGGCGAGUGAGGUCU AAGGACGU 7828
604 CUCGGGGA G CUGCAGGA 1797 UCCUGCAG GCCGAAAGGCGAGUGAGGUCU UCCCCGAG 7829
607 GGGGAGCU G CAGGAGAG 1798 CUCUCCUG GCCGAAAGGCGAGUGAGGUCU AGCUCCCC 7830
615 GCAGGAGA G CCAGAGUC 1799 GACUCUGG GCCGAAAGGCGAGUGAGGUCU UCUCCUGC 7831
621 GAGCCAGA G UCGCUUGG 1800 CCAAGCGA GCCGAAAGGCGAGUGAGGUCU UCUGGCUC 7832
624 CCAGAGUC G CUUGGAGG 1801 CCUCCAAG GCCGAAAGGCGAGUGAGGUCU GACUCUGG 7833
632 GCUUGGAG G CUGCCACU 1802 AGUGGCAG GCCGAAAGGCGAGUGAGGUCU CUCCAAGC 7834
635 UGGAGGCU G CCACUAAG 1803 CUUAGUGG GCCGAAAGGCGAGUGAGGUCU AGCCUCCA 7835
648 UAAGGAAU G CCAGGCUC 1804 GAGCCUGG GCCGAAAGGCGAGUGAGGUCU AUUCCUUA 7836
653 AAUGCCAG G CUCUGGAG 1805 CUCCAGAG GCCGAAAGGCGAGUGAGGUCU CUGGCAUU 7837
663 UCUGGAGG G UCGGGCCC 1806 GGGCCCGA GCCGAAAGGCGAGUGAGGUCU CCUCCAGA 7838
668 AGGGUCGG G CCCGGGCG 1807 CGCCCGGG GCCGAAAGGCGAGUGAGGUCU CCGACCCU 7839
674 GGGCCCGG G CGGCCAGC 1808 GCUGGCCG GCCGAAAGGCGAGUGAGGUCU CCGGGCCC 7840
677 CCCGGGCG G CCAGCGAG 1809 CUCGCUGG GCCGAAAGGCGAGUGAGGUCU CGCCCGGG 7841
681 GGCGGCCA G CGAGCAGG 1810 CCUGCUCG GCCGAAAGGCGAGUGAGGUCU UGGCCGCC 7842
685 GCCAGCGA G CAGGCGCG 1811 CGCGCCUG GCCGAAAGGCGAGUGAGGUCU UCGCUGGC 7843
689 GCGAGCAG G CGCGGCAG 1812 CUGCCGCG GCCGAAAGGCGAGUGAGGUCU CUGCUCGC 7844
691 GAGCAGGC G CGGCAGCU 1813 AGCUGCCG GCCGAAAGGCGAGUGAGGUCU GCCUGCUC 7845
694 CAGGCGCG G CAGCUGGA 1814 UCCAGCUG GCCGAAAGGCGAGUGAGGUCU CGCGCCUG 7846
697 GCGCGGCA G CUGGAGAG 1815 CUCUCCAG GCCGAAAGGCGAGUGAGGUCU UGCCGCGC 7847
705 GCUGGAGA G UGAGCGCG 1816 CGCGCUCA GCCGAAAGGCGAGUGAGGUCU UCUCCAGC 7848
709 GAGAGUGA G CGCGAGGC 1817 GCCUCGCG GCCGAAAGGCGAGUGAGGUCU UCACUCUC 7849
711 GAGUGAGC G CGAGGCGC 1818 GCGCCUCG GCCGAAAGGCGAGUGAGGUCU GCUCACUC 7850
716 AGCGCGAG G CGCUGCAG 1819 CUGCAGCG GCCGAAAGGCGAGUGAGGUCU CUCGCGCU 7851 718 CGCGAGGC G CUGCAGCA 1820 UGCUGCAG GCCGAAAGGCGAGUGAGGUCU GCCUCGCG 7852
721 GAGGCGCU G CAGCAGCA 1821 UGCUGCUG GCCGAAAGGCGAGUGAGGUCU AGCGCCUC 7853
724 GCGCUGCA G CAGCAGCA 1822 UGCUGCUG GCCGAAAGGCGAGUGAGGUCU UGCAGCGC 7854
727 CUGCAGCA G CAGCACAG 1823 CUGUGCUG GCCGAAAGGCGAGUGAGGUCU UGCUGCAG 7855
730 CAGCAGCA G CACAGCGU 1824 ACGCUGUG GCCGAAAGGCGAGUGAGGUCU UGCUGCUG 7856
735 GCAGCACA G CGUGCAGG 1825 CCUGCACG GCCGAAAGGCGAGUGAGGUCU UGUGCUGC 7857
737 AGCACAGC G UGCAGGUG 1826 CACCUGCA GCCGAAAGGCGAGUGAGGUCU GCUGUGCU 7858
739 CACAGCGU G CAGGUGGA 1827 UCCACCUG GCCGAAAGGCGAGUGAGGUCU ACGCUGUG 7859
743 GCGUGCAG G UGGACCAG 1828 CUGGUCCA GCCGAAAGGCGAGUGAGGUCU CUGCACGC 7860
751 GUGGACCA G CUGCGCAU 1829 AUGCGCAG GCCGAAAGGCGAGUGAGGUCU UGGUCCAC 7861
754 GACCAGCU G CGCAUGCA 1830 UGCAUGCG GCCGAAAGGCGAGUGAGGUCU AGCUGGUC 7862
756 CCAGCUGC G CAUGCAGG 1831 CCUGCAUG GCCGAAAGGCGAGUGAGGUCU GCAGCUGG 7863
760 CUGCGCAU G CAGGGCCA 1832 UGGCCCUG GCCGAAAGGCGAGUGAGGUCU AUGCGCAG 7864
765 CAUGCAGG G CCAGAGCG 1833 CGCUCUGG GCCGAAAGGCGAGUGAGGUCU CCUGCAUG 7865
771 GGGCCAGA G CGUGGAGG 1834 CCUCCACG GCCGAAAGGCGAGUGAGGUCU UCUGGCCC 7866
773 GCCAGAGC G UGGAGGCC 1835 GGCCUCCA GCCGAAAGGCGAGUGAGGUCU GCUCUGGC 7867
779 GCGUGGAG G CCGCGCUC 1836 GAGCGCGG GCCGAAAGGCGAGUGAGGUCU CUCCACGC 7868
782 UGGAGGCC G CGCUCCGC 1837 GCGGAGCG GCCGAAAGGCGAGUGAGGUCU GGCCUCCA 7869
784 GAGGCCGC G CUCCGCAU 1838 AUGCGGAG GCCGAAAGGCGAGUGAGGUCU GCGGCCUC 7870
789 CGCGCUCC G CAUGGAGC 1839 GCUCCAUG GCCGAAAGGCGAGUGAGGUCU GGAGCGCG 7871
796 CGCAUGGA G CGCCAGGC 1840 GCCUGGCG GCCGAAAGGCGAGUGAGGUCU UCCAUGCG 7872
798 CAUGGAGC G CCAGGCCG 1841 CGGCCUGG GCCGAAAGGCGAGUGAGGUCU GCUCCAUG 7873
803 AGCGCCAG G CCGCCUCG 1842 CGAGGCGG GCCGAAAGGCGAGUGAGGUCU CUGGCGCU 7874
806 GCCAGGCC G CCUCGGAG 1843 CUCCGAGG GCCGAAAGGCGAGUGAGGUCU GGCCUGGC 7875
826 AAGAGGAA G CUGGCCCA 1844 UGGGCCAG GCCGAAAGGCGAGUGAGGUCU UUCCUCUU 7876
830 GGAAGCUG G CCCAGUUG 1845 CAACUGGG GCCGAAAGGCGAGUGAGGUCU CAGCUUCC 7877
835 CUGGCCCA G UUGCAGGU 1846 ACCUGCAA GCCGAAAGGCGAGUGAGGUCU UGGGCCAG 7878
838 GCCCAGUU G CAGGUGGC 1847 GCCACCUG GCCGAAAGGCGAGUGAGGUCU AACUGGGC 7879
842 AGUUGCAG G UGGCCUAU 1848 AUAGGCCA GCCGAAAGGCGAGUGAGGUCU CUGCAACU 7880
845 UGCAGGUG G CCUAUCAC 1849 GUGAUAGG GCCGAAAGGCGAGUGAGGUCU CACCUGCA 7881
856 UAUCACCA G CUCUUCCA 1850 UGGAAGAG GCCGAAAGGCGAGUGAGGUCU UGGUGAUA 7882
888 CAUCAAGA G CAGCGUGG 1851 CCACGCUG GCCGAAAGGCGAGUGAGGUCU UCUUGAUG 7883
891 CAAGAGCA G CGUGGUGG 1852 CCACCACG GCCGAAAGGCGAGUGAGGUCU UGCUCUUG 7884
893 AGAGCAGC G UGGUGGGC 1853 GCCCACCA GCCGAAAGGCGAGUGAGGUCU GCUGCUCU 7885
896 GCAGCGUG G UGGGCAGU 1854 ACUGCCCA GCCGAAAGGCGAGUGAGGUCU CACGCUGC 7886
900 CGUGGUGG G CAGUGAGC 1855 GCUCACUG GCCGAAAGGCGAGUGAGGUCU CCACCACG 7887
903 GGUGGGCA G UGAGCGGA 1856 UCCGCUCA GCCGAAAGGCGAGUGAGGUCU UGCCCACC 7888
907 GGCAGUGA G CGGAAGCG 1857 CGCUUCCG GCCGAAAGGCGAGUGAGGUCU UCACUGCC 7889
913 GAGCGGAA G CGAGGAAU 1858 AUUCCUCG GCCGAAAGGCGAGUGAGGUCU UUCCGCUC 7890
922 CGAGGAAU G CAGCUGGA 1859 UCCAGCUG GCCGAAAGGCGAGUGAGGUCU AUUCCUCG 7891
925 GGAAUGCA G CUGGAAGA 1860 UCUUCCAG GCCGAAAGGCGAGUGAGGUCU UGCAUUCC 7892
943 CUCAAACA G CAGCUCCA 1861 UGGAGCUG GCCGAAAGGCGAGUGAGGUCU UGUUUGAG 7893
946 AAACAGCA G CUCCAGCA 1862 UGCUGGAG GCCGAAAGGCGAGUGAGGUCU UGCUGUUU 7894
952 CAGCUCCA G CAGGCCGA 1863 UCGGCCUG GCCGAAAGGCGAGUGAGGUCU UGGAGCUG 7895
956 UCCAGCAG G CCGAGGAG 1864 CUCCUCGG GCCGAAAGGCGAGUGAGGUCU CUGCUGGA 7896
965 CCGAGGAG G CCCUGGUG 1865 CACCAGGG GCCGAAAGGCGAGUGAGGUCU CUCCUCGG 7897
971 AGGCCCUG G UGGCCAAA 1866 UUUGGCCA GCCGAAAGGCGAGUGAGGUCU CAGGGCCU 7898
97 CCCUGGUG G CCAAACAG 1867 CUGUUUGG GCCGAAAGGCGAGUGAGGUCU CACCAGGG 7899
986 AACAGGAG G UGAUCGAU 1868 AUCGAUCA GCCGAAAGGCGAGUGAGGUCU CUCCUGUU 7900
997 AUCGAUAA G CUGAAGGA 1869 UCCUUCAG GCCGAAAGGCGAGUGAGGUCU UUAUCGAU 7901
1010 AGGAGGAG G CCGAGCAG 1870 CUGCUCGG GCCGAAAGGCGAGUGAGGUCU CUCCUCCU 7902 1015 GAGGCCGA G CAGCACAA 1871 UUGUGCUG GCCGAAAGGCGAGUGAGGUCU UCGGCCUC 7903
1018 GCCGAGCA G CACAAGAU 1872 AUCUUGUG GCCGAAAGGCGAGUGAGGUCU UGCUCGGC 7904
1028 ACAAGAUU G UGAUGGAG 1873 CUCCAUCA GCCGAAAGGCGAGUGAGGUCU AAUCUUGU 7905
1040 UGGAGACC G UUCCGGUG 1874 CACCGGAA GCCGAAAGGCGAGUGAGGUCU GGUCUCCA 7906
1046 CCGUUCCG G UGCUGAAG 1875 CUUCAGCA GCCGAAAGGCGAGUGAGGUCU CGGAACGG 7907
1048 GUUCCGGU G CUGAAGGC 1876 GCCUUCAG GCCGAAAGGCGAGUGAGGUCU ACCGGAAC 7908
1055 UGCUGAAG G CCCAGGCG 1877 CGCCUGGG GCCGAAAGGCGAGUGAGGUCU CUUCAGCA 7909
1061 AGGCCCAG G CGGAUAUC 1878 GAUAUCCG GCCGAAAGGCGAGUGAGGUCU CUGGGCCU 7910
1076 UCUACAAG G CGGACUUC 1879 GAAGUCCG GCCGAAAGGCGAGUGAGGUCU CUUGUAGA 7911
1088 ACUUCCAG G CUGAGAGG 1880 CCUCUCAG GCCGAAAGGCGAGUGAGGUCU CUGGAAGU 7912
1096 GCUGAGAG G CAGGCCCG 1881 CGGGCCUG GCCGAAAGGCGAGUGAGGUCU CUCUCAGC 7913
1100 AGAGGCAG G CCCGGGAG 1882 CUCCCGGG GCCGAAAGGCGAGUGAGGUCU CUGCCUCU 7914 llll CGGGAGAA G CUGGCCGA 1883 UCGGCCAG GCCGAAAGGCGAGUGAGGUCU UUCUCCCG 7915
1115 AGAAGCUG G CCGAGAAG 1884 CUUCUCGG GCCGAAAGGCGAGUGAGGUCU CAGCUUCU 7916
1129 AAGAAGGA G CUCCUGCA 1885 UGCAGGAG GCCGAAAGGCGAGUGAGGUCU UCCUUCUU 7917
1135 GAGCUCCU G CAGGAGCA 1886 UGCUCCUG GCCGAAAGGCGAGUGAGGUCU AGGAGCUC 7918
1141 CUGCAGGA G CAGCUGGA 1887 UCCAGCUG GCCGAAAGGCGAGUGAGGUCU UCCUGCAG 7919
1144 CAGGAGCA G CUGGAGCA 1888 UGCUCCAG GCCGAAAGGCGAGUGAGGUCU UGCUCCUG 7920
1150 CAGCUGGA G CAGCUGCA 1889 UGGAGCUG GCCGAAAGGCGAGUGAGGUCU UCCAGCUG 7921
1153 CUGGAGCA G CUGCAGAG 1890 CUCUGCAG GCCGAAAGGCGAGUGAGGUCU UGCUCCAG 7922
1156 GAGCAGCU G CAGAGGGA 1891 UCCCUCUG GCCGAAAGGCGAGUGAGGUCU AGCUGCUC 7923
1165 CAGAGGGA G UACAGCAA 1892 UUGCUGUA GCCGAAAGGCGAGUGAGGUCU UCCCUCUG 7924
1170 GGAGUACA G CAAACUGA 1893 UCAGUUUG GCCGAAAGGCGAGUGAGGUCU UGUACUCC 7925
1181 AACUGAAG G CCAGCUGU 1894 ACAGCUGG GCCGAAAGGCGAGUGAGGUCU CUUCAGUU 7926
1185 GAAGGCCA G CUGUCAGG 1895 CCUGACAG GCCGAAAGGCGAGUGAGGUCU UGGCCUUC 7927
1188 GGCCAGCU G UCAGGAGU 1896 ACUCCUGA GCCGAAAGGCGAGUGAGGUCU AGCUGGCC 7928
1195 UGUCAGGA G UCGGCCAG 1897 CUGGCCGA GCCGAAAGGCGAGUGAGGUCU UCCUGACA 7929
1199 AGGAGUCG G CCAGGAUC 1898 GAUCCUGG GCCGAAAGGCGAGUGAGGUCU CGACUCCU 7930
1222 AUGAGGAA G CGGCAUGU 1899 ACAUGCCG GCCGAAAGGCGAGUGAGGUCU UUCCUCAU 7931
1225 AGGAAGCG G CAUGUCGA 1900 UCGACAUG GCCGAAAGGCGAGUGAGGUCU CGCUUCCU 7932
1229 AGCGGCAU G UCGAGGUC 1901 GACCUCGA GCCGAAAGGCGAGUGAGGUCU AUGCCGCU 7933
1235 AUGUCGAG G UCUCCCAG 1902 CUGGGAGA GCCGAAAGGCGAGUGAGGUCU CUCGACAU 7934
1244 UCUCCCAG G CCCCCUUG 1903 CAAGGGGG GCCGAAAGGCGAGUGAGGUCU CUGGGAGA 7935
1252 GCCCCCUU G CCCCCCGC 1904 GCGGGGGG GCCGAAAGGCGAGUGAGGUCU AAGGGGGC 7936
1259 UGCCCCCC G CCCCUGCC 1905 GGCAGGGG GCCGAAAGGCGAGUGAGGUCU GGGGGGCA 7937
1265 CCGCCCCU G CCUACCUC 1906 GAGGUAGG GCCGAAAGGCGAGUGAGGUCU AGGGGCGG 7938
1286 CUCCCCUG G CCCUGCCC 1907 GGGCAGGG GCCGAAAGGCGAGUGAGGUCU CAGGGGAG 7939
1291 CUGGCCCU G CCCAGCCA 1908 UGGCUGGG GCCGAAAGGCGAGUGAGGUCU AGGGCCAG 7940
1296 CCUGCCCA G CCAGAGGA 1909 UCCUCUGG GCCGAAAGGCGAGUGAGGUCU UGGGCAGG 7941
1308 GAGGAGGA G CCCCCCCG 1910 CGGGGGGG GCCGAAAGGCGAGUGAGGUCU UCCUCCUC 7942
1321 CCCGAGGA G CCACCUGA 1911 UCAGGUGG GCCGAAAGGCGAGUGAGGUCU UCCUCGGG 7943
1335 UGACUUCU G CUGUCCCA 1912 UGGGACAG GCCGAAAGGCGAGUGAGGUCU AGAAGUCA 7944
1338 CUUCUGCU G UCCCAAGU 1913 ACUUGGGA GCCGAAAGGCGAGUGAGGUCU AGCAGAAG 7945
1345 UGUCCCAA G UGCCAGUA 1914 UACUGGCA GCCGAAAGGCGAGUGAGGUCU UUGGGACA 7946
1347 UCCCAAGU G CCAGUAUC 1915 GAUACUGG GCCGAAAGGCGAGUGAGGUCU ACUUGGGA 7947
1351 AAGUGCCA G UAUCAGGC 1916 GCCUGAUA GCCGAAAGGCGAGUGAGGUCU UGGCACUU 7948
1358 AGUAUCAG G CCCCUGAU 1917 AUCAGGGG GCCGAAAGGCGAGUGAGGUCU CUGAUACU 7949
1378 GACACCCU G CAGAUACA 1918 UGUAUCUG GCCGAAAGGCGAGUGAGGUCU AGGGUGUC 7950
1388 AGAUACAU G UCAUGGAG 1919 CUCCAUGA GCCGAAAGGCGAGUGAGGUCU AUGUAUCU 7951
1396 GUCAUGGA G UGCAUUGA 1920 UCAAUGCA GCCGAAAGGCGAGUGAGGUCU UCCAUGAC 7952
1398 CAUGGAGU G CAUUGAGU 1921 ACUCAAUG GCCGAAAGGCGAGUGAGGUCU ACUCCAUG 7953 1405 UGCAUUGA G UAGGGCCG 1922 CGGCCCUA GCCGAAAGGCGAGUGAGGUCU UCAAUGCA 7954
1410 UGAGUAGG G CCGGCCAG 1923 CUGGCCGG GCCGAAAGGCGAGUGAGGUCU CCUACUCA 7955
1414 UAGGGCCG G CCAGUGCA 1924 UGCACUGG GCCGAAAGGCGAGUGAGGUCU CGGCCCUA 7956
1418 GCCGGCCA G UGCAAGGC 1925 GCCUUGCA GCCGAAAGGCGAGUGAGGUCU UGGCCGGC 7957
1420 CGGCCAGU G CAAGGCCA 1926 UGGCCUUG GCCGAAAGGCGAGUGAGGUCU ACUGGCCG 7958
1425 AGUGCAAG G CCACUGCC 1927 GGCAGUGG GCCGAAAGGCGAGUGAGGUCU CUUGCACU 7959
1431 AGGCCACU G CCUGCCCG 1928 CGGGCAGG GCCGAAAGGCGAGUGAGGUCU AGUGGCCU 7960
1435 CACUGCCU G CCCGAGGA 1929 UCCUCGGG GCCGAAAGGCGAGUGAGGUCU AGGCAGUG 7961
1445 CCGAGGAC G UGCCCGGG 1930 CCCGGGCA GCCGAAAGGCGAGUGAGGUCU GUCCUCGG 7962
1447 GAGGACGU G CCCGGGAC 1931 GUCCCGGG GCCGAAAGGCGAGUGAGGUCU ACGUCCUC 7963
1457 CCGGGACC G UGCAGUCU 1932 AGACUGCA GCCGAAAGGCGAGUGAGGUCU GGUCCCGG 7964
1459 GGGACCGU G CAGUCUGC 1933 GCAGACUG GCCGAAAGGCGAGUGAGGUCU ACGGUCCC 7965
1462 ACCGUGCA G UCUGCGCU 1934 AGCGCAGA GCCGAAAGGCGAGUGAGGUCU UGCACGGU 7966
1466 UGCAGUCU G CGCUUUCC 1935 GGAAAGCG GCCGAAAGGCGAGUGAGGUCU AGACUGCA 7967
1468 CAGUCUGC G CUUUCCUC 1936 GAGGAAAG GCCGAAAGGCGAGUGAGGUCU GCAGACUG 7968
1481 CCUCUCCC G CCUGCCUA 1937 UAGGCAGG GCCGAAAGGCGAGUGAGGUCU GGGAGAGG 7969
1485 UCCCGCCU G CCUAGCCC 1938 GGGCUAGG GCCGAAAGGCGAGUGAGGUCU AGGCGGGA 7970
1490 CCUGCCUA G CCCAGGAU 1939 AUCCUGGG GCCGAAAGGCGAGUGAGGUCU UAGGCAGG 7971
1504 GAUGAAGG G CUGGGUGG 1940 CCACCCAG GCCGAAAGGCGAGUGAGGUCU CCUUCAUC 7972
1509 AGGGCUGG G UGGCCACA 1941 UGUGGCCA GCCGAAAGGCGAGUGAGGUCU CCAGCCCU 7973
1512 GCUGGGUG G CCACAACU 1942 AGUUGUGG GCCGAAAGGCGAGUGAGGUCU CACCCAGC 7974
1526 ACUGGGAU G CCACCUGG 1943 CCAGGUGG GCCGAAAGGCGAGUGAGGUCU AUCCCAGU 7975
1536 CACCUGGA G CCCCACCC 1944 GGGUGGGG GCCGAAAGGCGAGUGAGGUCU UCCAGGUG 7976
1549 ACCCAGGA G CUGGCCGC 1945 GCGGCCAG GCCGAAAGGCGAGUGAGGUCU UCCUGGGU 7977
1553 AGGAGCUG G CCGCGGCA 1946 UGCCGCGG GCCGAAAGGCGAGUGAGGUCU CAGCUCCU 7978
1556 AGCUGGCC G CGGCACCU 1947 AGGUGCCG GCCGAAAGGCGAGUGAGGUCU GGCCAGCU 7979
1559 UGGCCGCG G CACCUUAC 1948 GUAAGGUG GCCGAAAGGCGAGUGAGGUCU CGCGGCCA 7980
1568 CACCUUAC G CUUCAGCU 1949 AGCUGAAG GCCGAAAGGCGAGUGAGGUCU GUAAGGUG 7981
1574 ACGCUUCA G CUGUUGAU 1950 AUCAACAG GCCGAAAGGCGAGUGAGGUCU UGAAGCGU 7982
1577 CUUCAGCU G UUGAUCCG 1951 CGGAUCAA GCCGAAAGGCGAGUGAGGUCU AGCUGAAG 7983
1585 GUUGAUCC G CUGGUCCC 1952 GGGACCAG GCCGAAAGGCGAGUGAGGUCU GGAUCAAC 7984
1589 AUCCGCUG G UCCCCUCU 1953 AGAGGGGA GCCGAAAGGCGAGUGAGGUCU CAGCGGAU 7985
1604 CUUUUGGG G UAGAUGCG 1954 CGCAUCUA GCCGAAAGGCGAGUGAGGUCU CCCAAAAG 7986
1610 GGGUAGAU G CGGCCCCG 1955 CGGGGCCG GCCGAAAGGCGAGUGAGGUCU AUCUACCC 7987
1613 UAGAUGCG G CCCCGAUC 1956 GAUCGGGG GCCGAAAGGCGAGUGAGGUCU CGCAUCUA 7988
1624 CCGAUCAG G CCUGACUC 1957 GAGUCAGG GCCGAAAGGCGAGUGAGGUCU CUGAUCGG 7989
1633 CCUGACUC G CUGCUCUU 1958 AAGAGCAG GCCGAAAGGCGAGUGAGGUCU GAGUCAGG 7990
1636 GACUCGCU G CUCUUUUU 1959 AAAAAGAG GCCGAAAGGCGAGUGAGGUCU AGCGAGUC 7991
1645 CUCUUUUU G UUCCCUUC 1960 GAAGGGAA GCCGAAAGGCGAGUGAGGUCU AAAAAGAG 7992
1655 UCCCUUCU G UCUGCUCG 1961 CGAGCAGA GCCGAAAGGCGAGUGAGGUCU AGAAGGGA 7993
1659 UUCUGUCU G CUCGAACC 1962 GGUUCGAG GCCGAAAGGCGAGUGAGGUCU AGACAGAA 7994
1672 AACCACUU G CCUCGGGC 1963 GCCCGAGG GCCGAAAGGCGAGUGAGGUCU AAGUGGUU 7995
1679 UGCCUCGG G CUAAUCCC 1964 GGGAUUAG GCCGAAAGGCGAGUGAGGUCU CCGAGGCA 7996
1706 UCCACCCG G CACUGGGG 1965 CCCCAGUG GCCGAAAGGCGAGUGAGGUCU CGGGUGGA 7997
1717 CUGGGGAA G UCAAGAAU 1966 AUUCUUGA GCCGAAAGGCGAGUGAGGUCU UUCCCCAG 7998
1729 AGAAUGGG G CCUGGGGC 1967 GCCCCAGG GCCGAAAGGCGAGUGAGGUCU CCCAUUCU 7999
1736 GGCCUGGG G CUCUCAGG 1968 CCUGAGAG GCCGAAAGGCGAGUGAGGUCU CCCAGGCC 8000
1752 GGAGAACU G CUUCCCCU 1969 AGGGGAAG GCCGAAAGGCGAGUGAGGUCU AGUUCUCC 8001
1762 UUCCCCUG G CAGAGCUG 1970 CAGCUCUG GCCGAAAGGCGAGUGAGGUCU CAGGGGAA 8002
1767 CUGGCAGA G CUGGGUGG 1971 CCACCCAG GCCGAAAGGCGAGUGAGGUCU UCUGCCAG 8003
1772 AGAGCUGG G UGGCAGCU 1972 AGCUGCCA GCCGAAAGGCGAGUGAGGUCU CCAGCUCU 8004 1775 GCUGGGUG G CAGCUCUU 1973 AAGAGCUG GCCGAAAGGCGAGUGAGGUCU CACCCAGC 8005
1778 GGGUGGCA G CUCUUCCU 1974 AGGAAGAG GCCGAAAGGCGAGUGAGGUCU UGCCACCC 8006
1805 ACCGACCC G CCCGCCGC 1975 GCGGCGGG GCCGAAAGGCGAGUGAGGUCU GGGUCGGU 8007
1809 ACCCGCCC G CCGCUGUG 1976 CACAGCGG GCCGAAAGGCGAGUGAGGUCU GGGCGGGU 8008
1812 CGCCCGCC G CUGUGCCC 1977 GGGCACAG GCCGAAAGGCGAGUGAGGUCU GGCGGGCG 8009
1815 CCGCCGCU G UGCCCUGG 1978 CCAGGGCA GCCGAAAGGCGAGUGAGGUCU AGCGGCGG 8010
1817 GCCGCUGU G CCCUGGGA 1979 UCCCAGGG GCCGAAAGGCGAGUGAGGUCU ACAGCGGC 8011
1826 CCCUGGGA G UGCUGCCC 1980 GGGCAGCA GCCGAAAGGCGAGUGAGGUCU UCCCAGGG 8012
1828 CUGGGAGU G CUGCCCUC 1981 GAGGGCAG GCCGAAAGGCGAGUGAGGUCU ACUCCCAG 8013
1831 GGAGUGCU G CCCUCUUA 1982 UAAGAGGG GCCGAAAGGCGAGUGAGGUCU AGCACUCC 8014
1844 CUUACCAU G CACACGGG 1983 CCCGUGUG GCCGAAAGGCGAGUGAGGUCU AUGGUAAG 8015
1852 GCACACGG G UGCUCUCC 1984 GGAGAGCA GCCGAAAGGCGAGUGAGGUCU CCGUGUGC 8016
1854 ACACGGGU G CUCUCCUU 1985 AAGGAGAG GCCGAAAGGCGAGUGAGGUCU ACCCGUGU 8017
1867 CCUUUUGG G CUGCAUGC 1986 GCAUGCAG GCCGAAAGGCGAGUGAGGUCU CCAAAAGG 8018
1870 UUUGGGCU G CAUGCUAU 1987 AUAGCAUG GCCGAAAGGCGAGUGAGGUCU AGCCCAAA 8019
1874 GGCUGCAU G CUAUUCCA 1988 UGGAAUAG GCCGAAAGGCGAGUGAGGUCU AUGCAGCC 8020
1887 UCCAUUUU G CAGCCAGA 1989 UCUGGCUG GCCGAAAGGCGAGUGAGGUCU AAAAUGGA 8021
1890 AUUUUGCA G CCAGACCG 1990 CGGUCUGG GCCGAAAGGCGAGUGAGGUCU UGCAAAAU 8022
1901 AGACCGAU G UGUAUUUA 1991 UAAAUACA GCCGAAAGGCGAGUGAGGUCU AUCGGUCU 8023
1903 ACCGAUGU G UAUUUAAC 1992 GUUAAAUA GCCGAAAGGCGAGUGAGGUCU ACAUCGGU 8024
1914 UUUAACCA G UCACUAUU 1993 AAUAGUGA GCCGAAAGGCGAGUGAGGUCU UGGUUAAA 8025
1936 ACAUUUGG G UUGUUUCC 1994 GGAAACAA GCCGAAAGGCGAGUGAGGUCU CCAAAUGU 8026
1939 UUUGGGUU G UUUCCCAU 1995 AUGGGAAA GCCGAAAGGCGAGUGAGGUCU AACCCAAA 8027
1954 AUCUUUUU G UUACCAUA 1996 UAUGGUAA GCCGAAAGGCGAGUGAGGUCU AAAAAGAU 8028
1970 AAAUAAUG G CAUAGUAA 1997 UUACUAUG GCCGAAAGGCGAGUGAGGUCU CAUUAUUU 8029
1975 AUGGCAUA G UAAAAAAA 1998 UUUUUUUA GCCGAAAGGCGAGUGAGGUCU UAUGCCAU 8030
Input Sequence = NM_003639. Cut Site = G/Y
Arm Length = 8. Core Sequence = GCcgaaagGCGaGuCaaGGuCu
NM_003639 (Homo sapiens inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma (IKBKG), mRNA.; 1994 bp)
Table XI: Human IKK-gamma DNAzyme and Substrate Sequence
Pos Substrate Seq DNAzyme Seq
ID ID
10 GCACGAGC A UGGCCCUU 1218 AAGGGCCA GGCTAGCTACAACGA GCTCGTGC 8031
13 CGAGCAUG G CCCUUGUG 1722 CACAAGGG GGCTAGCTACAACGA CATGCTCG 8032
19 UGGCCCUU G UGAUCCAG 1723 CTGGATCA GGCTAGCTACAACGA AAGGGCCA 8033
22 CCCUUGUG A UCCAGGUG 1999 CACCTGGA GGCTAGCTACAACGA CACAAGGG 8034
28 UGAUCCAG G UGGGGAAA 1724 TTTCCCCA GGCTAGCTACAACGA CTGGATCA 8035
36 GUGGGGAA A CUAAGGCC 2000 GGCCTTAG GGCTAGCTACAACGA TTCCCCAC 8036
42 AAACUAAG G CCCAGAGA 1725 TCTCTGGG GGCTAGCTACAACGA CTTAGTTT 8037
52 CCAGAGAA G UGAGGACC 1726 GGTCCTCA GGCTAGCTACAACGA TTCTCTGG 8038
58 AAGUGAGG A CCCCGCAG 2001 CTGCGGGG GGCTAGCTACAACGA CCTCACTT 8039
63 AGGACCCC G CAGACUAU 1727 ATAGTCTG GGCTAGCTACAACGA GGGGTCCT 8040
67 CCCCGCAG A CUAUCAAU 2002 ATTGATAG GGCTAGCTACAACGA CTGCGGGG 8041
70 CGCAGACU A UCAAUCCC 1027 GGGATTGA GGCTAGCTACAACGA AGTCTGCG 8042
74 GACUAUCA A UCCCAGUC 2003 GACTGGGA GGCTAGCTACAACGA TGATAGTC 8043
80 CAAUCCCA G UCUCUUCC 1728 GGAAGAGA GGCTAGCTACAACGA TGGGATTG 8044
93 UUCCCCUC A CUCCCUGU 1243 ACAGGGAG GGCTAGCTACAACGA GAGGGGAA 8045
100 CACUCCCU G UGAAGCUC 1729 GAGCTTCA GGCTAGCTACAACGA AGGGAGTG 8046
105 CCUGUGAA G CUCUCCAG 1730 CTGGAGAG GGCTAGCTACAACGA TTCACAGG 8047
113 GCUCUCCA G CAUCAUCG 1731 CGATGATG GGCTAGCTACAACGA TGGAGAGC 8048
115 UCUCCAGC A UCAUCGAG 1252 CTCGATGA GGCTAGCTACAACGA GCTGGAGA 8049
118 CCAGCAUC A UCGAGGUC 1253 GACCTCGA GGCTAGCTACAACGA GATGCTGG 8050
124 UCAUCGAG G UCCCAUCA 1732 TGATGGGA GGCTAGCTACAACGA CTCGATGA 8051
129 GAGGUCCC A UCAGCCCU 1256 AGGGCTGA GGCTAGCTACAACGA GGGACCTC 8052
133 UCCCAUCA G CCCUUGCC 1733 GGCAAGGG GGCTAGCTACAACGA TGATGGGA 8053
139 CAGCCCUU G CCCUGUUG 1734 CAACAGGG GGCTAGCTACAACGA AAGGGCTG 8054
144 CUUGCCCU G UUGGAUGA 1735 TCATCCAA GGCTAGCTACAACGA AGGGCAAG 8055
149 CCUGUUGG A UGAAUAGG 2004 CCTATTCA GGCTAGCTACAACGA CCAACAGG 8056
153 UUGGAUGA A UAGGCACC 2005 GGTGCCTA GGCTAGCTACAACGA TCATCCAA 8057
157 AUGAAUAG G CACCUCUG 1736 CAGAGGTG GGCTAGCTACAACGA CTATTCAT 8058
159 GAAUAGGC A CCUCUGGA 1264 TCCAGAGG GGCTAGCTACAACGA GCCTATTC 8059
171 CUGGAAGA G CCAACUGU 1737 ACAGTTGG GGCTAGCTACAACGA TCTTCCAG 8060
175 AAGAGCCA A CUGUGUGA 2006 TCACACAG GGCTAGCTACAACGA TGGCTCTT 8061
178 AGCCAACU G UGUGAGAU 1738 ATCTCACA GGCTAGCTACAACGA AGTTGGCT 8062
180 CCAACUGU G UGAGAUGG 1739 CCATCTCA GGCTAGCTACAACGA ACAGTTGG 8063
185 UGUGUGAG A UGGUGCAG 2007 CTGCACCA GGCTAGCTACAACGA CTCACACA 8064
188 GUGAGAUG G UGCAGCCC 1740 GGGCTGCA GGCTAGCTACAACGA CATCTCAC 8065
190 GAGAUGGU G CAGCCCAG 1741 CTGGGCTG GGCTAGCTACAACGA ACCATCTC 8066
193 AUGGUGCA G CCCAGUGG 1742 CCACTGGG GGCTAGCTACAACGA TGCACCAT 8067
198 GCAGCCCA G UGGUGGCC 1743 GGCCACCA GGCTAGCTACAACGA TGGGCTGC 8068
201 GCCCAGUG G UGGCCCGG 1744 CCGGGCCA GGCTAGCTACAACGA CACTGGGC 8069
204 CAGUGGUG G CCCGGCAG 1745 CTGCCGGG GGCTAGCTACAACGA CACCACTG 8070
209 GUGGCCCG G CAGCAGAU 1746 ATCTGCTG GGCTAGCTACAACGA CGGGCCAC 8071
212 GCCCGGCA G CAGAUCAG 1747 CTGATCTG GGCTAGCTACAACGA TGCCGGGC 8072
216 GGCAGCAG A UCAGGACG 2008 CGTCCTGA GGCTAGCTACAACGA CTGCTGCC 8073
222 AGAUCAGG A CGUACUGG 2009 CCAGTACG GGCTAGCTACAACGA CCTGATCT 8074
224 AUCAGGAC G UACUGGGC 1748 GCCCAGTA GGCTAGCTACAACGA GTCCTGAT 8075
226 CAGGACGU A CUGGGCGA 1047 TCGCCCAG GGCTAGCTACAACGA ACGTCCTG 8076
231 CGUACUGG G CGAAGAGU 1749 ACTCTTCG GGCTAGCTACAACGA CCAGTACG 8077 238 GGCGAAGA G UCUCCUCU 1750 AGAGGAGA GGCTAGCTACAACGA TCTTCGCC 8078
253 CUGGGGAA G CCAGCCAU 1751 ATGGCTGG GGCTAGCTACAACGA TTCCCCAG 8079
257 GGAAGCCA G CCAUGCUG 1752 CAGCATGG GGCTAGCTACAACGA TGGCTTCC 8080
260 AGCCAGCC A UGCUGCAC 1288 GTGCAGCA GGCTAGCTACAACGA GGCTGGCT 8081
262 CCAGCCAU G CUGCACCU 1753 AGGTGCAG GGCTAGCTACAACGA ATGGCTGG 8082
265 GCCAUGCU G CACCUGCC 1754 GGCAGGTG GGCTAGCTACAACGA AGCATGGC 8083
267 CAUGCUGC A CCUGCCUU 1290 AAGGCAGG GGCTAGCTACAACGA GCAGCATG 8084
271 CUGCACCU G CCUUCAGA 1755 TCTGAAGG GGCTAGCTACAACGA AGGTGCAG 8085
280 CCUUCAGA A CAGGGCGC 2010 GCGCCCTG GGCTAGCTACAACGA TCTGAAGG 8086
285 AGAACAGG G CGCUCCUG 1756 CAGGAGCG GGCTAGCTACAACGA CCTGTTCT 8087
287 AACAGGGC G CUCCUGAG 1757 CTCAGGAG GGCTAGCTACAACGA GCCCTGTT 8088
296 CUCCUGAG A CCCUCCAG 2011 CTGGAGGG GGCTAGCTACAACGA CTCAGGAG 8089
304 ACCCUCCA G CGCUGCCU 1758 AGGCAGCG GGCTAGCTACAACGA TGGAGGGT 8090
306 CCUCCAGC G CUGCCUGG 1759 CCAGGCAG GGCTAGCTACAACGA GCTGGAGG 8091
309 CCAGCGCU G CCUGGAGG 1760 CCTCCAGG GGCTAGCTACAACGA AGCGCTGG 8092
321 GGAGGAGA A UCAAGAGC 2012 GCTCTTGA GGCTAGCTACAACGA TCTCCTCC 8093
328 AAUCAAGA G CUCCGAGA 1761 TCTCGGAG GGCTAGCTACAACGA TCTTGATT 8094
336 GCUCCGAG A UGCCAUCC 2013 GGATGGCA GGCTAGCTACAACGA CTCGGAGC 8095
338 UCCGAGAU G CCAUCCGG 1762 CCGGATGG GGCTAGCTACAACGA ATCTCGGA 8096
341 GAGAUGCC A UCCGGCAG 1312 CTGCCGGA GGCTAGCTACAACGA GGCATCTC 8097
346 GCCAUCCG G CAGAGCAA 1763 TTGCTCTG GGCTAGCTACAACGA CGGATGGC 8098
351 CCGGCAGA G CAACCAGA 1764 TCTGGTTG GGCTAGCTACAACGA TCTGCCGG 8099
354 GCAGAGCA A CCAGAUUC 2014 GAATCTGG GGCTAGCTACAACGA TGCTCTGC 8100
359 GCAACCAG A UUCUGCGG 2015 CCGCAGAA GGCTAGCTACAACGA CTGGTTGC 8101
364 CAGAUUCU G CGGGAGCG 1765 CGCTCCCG GGCTAGCTACAACGA AGAATCTG 8102
370 CUGCGGGA G CGCUGCGA 1766 TCGCAGCG GGCTAGCTACAACGA TCCCGCAG 8103
372 GCGGGAGC G CUGCGAGG 1767 CCTCGCAG GGCTAGCTACAACGA GCTCCCGC 8104
375 GGAGCGCU G CGAGGAGC 1768 GCTCCTCG GGCTAGCTACAACGA AGCGCTCC 8105
382 UGCGAGGA G CUUCUGCA 1769 TGCAGAAG GGCTAGCTACAACGA TCCTCGCA 8106
388 GAGCUUCU G CAUUUCCA 1770 TGGAAATG GGCTAGCTACAACGA AGAAGCTC 8107
390 GCUUCUGC A UUUCCAAG 1322 CTTGGAAA GGCTAGCTACAACGA GCAGAAGC 8108
398 AUUUCCAA G CCAGCCAG 1771 CTGGCTGG GGCTAGCTACAACGA TTGGAAAT 8109
402 CCAAGCCA G CCAGAGGG 1772 CCCTCTGG GGCTAGCTACAACGA TGGCTTGG 8110
421 GAGAAGGA G UUCCUCAU 1773 ATGAGGAA GGCTAGCTACAACGA TCCTTCTC 8111
428 AGUUCCUC A UGUGCAAG 1331 CTTGCACA GGCTAGCTACAACGA GAGGAACT 8112
430 UUCCUCAU G UGCAAGUU 1774 AACTTGCA GGCTAGCTACAACGA ATGAGGAA 8113
432 CCUCAUGU G CAAGUUCC 1775 GGAACTTG GGCTAGCTACAACGA ACATGAGG 8114
436 AUGUGCAA G UUCCAGGA 1776 TCCTGGAA GGCTAGCTACAACGA TTGCACAT 8115
446 UCCAGGAG G CCAGGAAA 1777 TTTCCTGG GGCTAGCTACAACGA CTCCTGGA 8116
454 GCCAGGAA A CUGGUGGA 2016 TCCACCAG GGCTAGCTACAACGA TTCCTGGC 8117
458 GGAAACUG G UGGAGAGA 1778 TCTCTCCA GGCTAGCTACAACGA CAGTTTCC 8118
466 GUGGAGAG A CUCGGCCU 2017 AGGCCGAG GGCTAGCTACAACGA CTCTCCAC 8119
471 GAGACUCG G CCUGGAGA 1779 TCTCCAGG GGCTAGCTACAACGA CGAGTCTC 8120
481 CUGGAGAA G CUCGAUCU 1780 AGATCGAG GGCTAGCTACAACGA TTCTCCAG 8121
486 GAAGCUCG A UCUGAAGA 2018 TCTTCAGA GGCTAGCTACAACGA CGAGCTTC 8122
496 CUGAAGAG G CAGAAGGA 1781 TCCTTCTG GGCTAGCTACAACGA CTCTTCAG 8123
505 CAGAAGGA G CAGGCUCU 1782 AGAGCCTG GGCTAGCTACAACGA TCCTTCTG 8124
509 AGGAGCAG G CUCUGCGG 1783 CCGCAGAG GGCTAGCTACAACGA CTGCTCCT 8125
514 CAGGCUCU G CGGGAGGU 1784 ACCTCCCG GGCTAGCTACAACGA AGAGCCTG 8126
521 UGCGGGAG G UGGAGCAC 1785 GTGCTCCA GGCTAGCTACAACGA CTCCCGCA 8127
526 GAGGUGGA G CACCUGAA 1786 TTCAGGTG GGCTAGCTACAACGA TCCACCTC 8128 528 GGUGGAGC A CCUGAAGA 1347 TCTTCAGG GGCTAGCTACAACGA GCTCCACC 8129
538 CUGAAGAG A UGCCAGCA 2019 TGCTGGCA GGCTAGCTACAACGA CTCTTCAG 8130
540 GAAGAGAU G CCAGCAGC 1787 GCTGCTGG GGCTAGCTACAACGA ATCTCTTC 8131
544 AGAUGCCA G CAGCAGAU 1788 ATCTGCTG GGCTAGCTACAACGA TGGCATCT 8132
547 UGCCAGCA G CAGAUGGC 1789 GCCATCTG GGCTAGCTACAACGA TGCTGGCA 8133
551 AGCAGCAG A UGGCUGAG 2020 CTCAGCCA GGCTAGCTACAACGA CTGCTGCT 8134
554 AGCAGAUG G CUGAGGAC 1790 GTCCTCAG GGCTAGCTACAACGA CATCTGCT 8135
561 GGCUGAGG A CAAGGCCU 2021 AGGCCTTG GGCTAGCTACAACGA CCTCAGCC 8136
566 AGGACAAG G CCUCUGUG 1791 CACAGAGG GGCTAGCTACAACGA CTTGTCCT 8137
572 AGGCCUCU G UGAAAGCC 1792 GGCTTTCA GGCTAGCTACAACGA AGAGGCCT 8138
578 CUGUGAAA G CCCAGGUG 1793 CACCTGGG GGCTAGCTACAACGA TTTCACAG 8139
584 AAGCCCAG G UGACGUCC 1794 GGACGTCA GGCTAGCTACAACGA CTGGGCTT 8140
587 CCCAGGUG A CGUCCUUG 2022 CAAGGACG GGCTAGCTACAACGA CACCTGGG 8141
589 CAGGUGAC G UCCUUGCU 1795 AGCAAGGA GGCTAGCTACAACGA GTCACCTG 8142
595 ACGUCCUU G CUCGGGGA 1796 TCCCCGAG GGCTAGCTACAACGA AAGGACGT 8143
604 CUCGGGGA G CUGCAGGA 1797 TCCTGCAG GGCTAGCTACAACGA TCCCCGAG 8144
607 GGGGAGCU G CAGGAGAG 1798 CTCTCCTG GGCTAGCTACAACGA AGCTCCCC 8145
615 GCAGGAGA G CCAGAGUC 1799 GACTCTGG GGCTAGCTACAACGA TCTCCTGC 8146
621 GAGCCAGA G UCGCUUGG 1800 CCAAGCGA GGCTAGCTACAACGA TCTGGCTC 8147
624 CCAGAGUC G CUUGGAGG 1801 CCTCCAAG GGCTAGCTACAACGA GACTCTGG 8148
632 GCUUGGAG G CUGCCACU 1802 AGTGGCAG GGCTAGCTACAACGA CTCCAAGC 8149
635 UGGAGGCU G CCACUAAG 1803 CTTAGTGG GGCTAGCTACAACGA AGCCTCCA 8150
638 AGGCUGCC A CUAAGGAA 1372 TTCCTTAG GGCTAGCTACAACGA GGCAGCCT 8151
646 ACUAAGGA A UGCCAGGC 2023 GCCTGGCA GGCTAGCTACAACGA TCCTTAGT 8152
648 UAAGGAAU G CCAGGCUC 1804 GAGCCTGG GGCTAGCTACAACGA ATTCCTTA 8153
653 AAUGCCAG G CUCUGGAG 1805 CTCCAGAG GGCTAGCTACAACGA CTGGCATT 8154
663 UCUGGAGG G UCGGGCCC 1806 GGGCCCGA GGCTAGCTACAACGA CCTCCAGA 8155
668 AGGGUCGG G CCCGGGCG 1807 CGCCCGGG GGCTAGCTACAACGA CCGACCCT 8156
674 GGGCCCGG G CGGCCAGC 1808 GCTGGCCG GGCTAGCTACAACGA CCGGGCCC 8157
677 CCCGGGCG G CCAGCGAG 1809 CTCGCTGG GGCTAGCTACAACGA CGCCCGGG 8158
681 GGCGGCCA G CGAGCAGG 1810 CCTGCTCG GGCTAGCTACAACGA TGGCCGCC 8159
685 GCCAGCGA G CAGGCGCG 1811 CGCGCCTG GGCTAGCTACAACGA TCGCTGGC 8160
689 GCGAGCAG G CGCGGCAG 1812 CTGCCGCG GGCTAGCTACAACGA CTGCTCGC 8161
691 GAGCAGGC G CGGCAGCU 1813 AGCTGCCG GGCTAGCTACAACGA GCCTGCTC 8162
694 CAGGCGCG G CAGCUGGA 1814 TCCAGCTG GGCTAGCTACAACGA CGCGCCTG 8163
697 GCGCGGCA G CUGGAGAG 1815 CTCTCCAG GGCTAGCTACAACGA TGCCGCGC 8164
705 GCUGGAGA G UGAGCGCG 1816 CGCGCTCA GGCTAGCTACAACGA TCTCCAGC 8165
709 GAGAGUGA G CGCGAGGC 1817 GCCTCGCG GGCTAGCTACAACGA TCACTCTC 8166
711 GAGUGAGC G CGAGGCGC 1818 GCGCCTCG GGCTAGCTACAACGA GCTCACTC 8167
716 AGCGCGAG G CGCUGCAG 1819 CTGCAGCG GGCTAGCTACAACGA CTCGCGCT 8168
718 CGCGAGGC G CUGCAGCA 1820 TGCTGCAG GGCTAGCTACAACGA GCCTCGCG 8169
721 GAGGCGCU G CAGCAGCA 1821 TGCTGCTG GGCTAGCTACAACGA AGCGCCTC 8170
724 GCGCUGCA G CAGCAGCA 1822 TGCTGCTG GGCTAGCTACAACGA TGCAGCGC 8171
727 CUGCAGCA G CAGCACAG 1823 CTGTGCTG GGCTAGCTACAACGA TGCTGCAG 8172
730 CAGCAGCA G CACAGCGU 1824 ACGCTGTG GGCTAGCTACAACGA TGCTGCTG 8173
732 GCAGCAGC A CAGCGUGC 1389 GCACGCTG GGCTAGCTACAACGA GCTGCTGC 8174
735 GCAGCACA G CGUGCAGG 1825 CCTGCACG GGCTAGCTACAACGA TGTGCTGC 8175
737 AGCACAGC G UGCAGGUG 1826 CACCTGCA GGCTAGCTACAACGA GCTGTGCT 8176
739 CACAGCGU G CAGGUGGA 1827 TCCACCTG GGCTAGCTACAACGA ACGCTGTG 8177
743 GCGUGCAG G UGGACCAG 1828 CTGGTCCA GGCTAGCTACAACGA CTGCACGC 8178
747 GCAGGUGG A CCAGCUGC 2024 GCAGCTGG GGCTAGCTACAACGA CCACCTGC 8179 751 GUGGACCA G CUGCGCAU 1829 ATGCGCAG GGCTAGCTACAACGA TGGTCCAC 8180
754 GACCAGCU G CGCAUGCA 1830 TGCATGCG GGCTAGCTACAACGA AGCTGGTC 8181
756 CCAGCUGC G CAUGCAGG 1831 CCTGCATG GGCTAGCTACAACGA GCAGCTGG 8182
758 AGCUGCGC A UGCAGGGC 1395 GCCCTGCA GGCTAGCTACAACGA GCGCAGCT 8183
760 CUGCGCAU G CAGGGCCA 1832 TGGCCCTG GGCTAGCTACAACGA ATGCGCAG 8184
765 CAUGCAGG G CCAGAGCG 1833 CGCTCTGG GGCTAGCTACAACGA CCTGCATG 8185
771 GGGCCAGA G CGUGGAGG 1834 CCTCCACG GGCTAGCTACAACGA TCTGGCCC 8186
773 GCCAGAGC G UGGAGGCC 1835 GGCCTCCA GGCTAGCTACAACGA GCTCTGGC 8187
779 GCGUGGAG G CCGCGCUC 1836 GAGCGCGG GGCTAGCTACAACGA CTCCACGC 8188
782 UGGAGGCC G CGCUCCGC 1837 GCGGAGCG GGCTAGCTACAACGA GGCCTCCA 8189
784 GAGGCCGC G CUCCGCAU 1838 ATGCGGAG GGCTAGCTACAACGA GCGGCCTC 8190
789 CGCGCUCC G CAUGGAGC 1839 GCTCCATG GGCTAGCTACAACGA GGAGCGCG 8191
791 CGCUCCGC A UGGAGCGC 1402 GCGCTCCA GGCTAGCTACAACGA GCGGAGCG 8192
796 CGCAUGGA G CGCCAGGC 1840 GCCTGGCG GGCTAGCTACAACGA TCCATGCG 8193
798 CAUGGAGC G CCAGGCCG 1841 CGGCCTGG GGCTAGCTACAACGA GCTCCATG 8194
803 AGCGCCAG G CCGCCUCG 1842 CGAGGCGG GGCTAGCTACAACGA CTGGCGCT 8195
806 GCCAGGCC G CCUCGGAG 1843 CTCCGAGG GGCTAGCTACAACGA GGCCTGGC 8196
826 AAGAGGAA G CUGGCCCA 1844 TGGGCCAG GGCTAGCTACAACGA TTCCTCTT 8197
830 GGAAGCUG G CCCAGUUG 1845 CAACTGGG GGCTAGCTACAACGA CAGCTTCC 8198
835 CUGGCCCA G UUGCAGGU 1846 ACCTGCAA GGCTAGCTACAACGA TGGGCCAG 8199
838 GCCCAGUU G CAGGUGGC 1847 GCCACCTG GGCTAGCTACAACGA AACTGGGC 8200
842 AGUUGCAG G UGGCCUAU 1848 ATAGGCCA GGCTAGCTACAACGA CTGCAACT 8201
845 UGCAGGUG G CCUAUCAC 1849 GTGATAGG GGCTAGCTACAACGA CACCTGCA 8202
849 GGUGGCCU A UCACCAGC 1086 GCTGGTGA GGCTAGCTACAACGA AGGCCACC 8203
852 GGCCUAUC A CCAGCUCU 1415 AGAGCTGG GGCTAGCTACAACGA GATAGGCC 8204
856 UAUCACCA G CUCUUCCA 1850 TGGAAGAG GGCTAGCTACAACGA TGGTGATA 8205
868 UUCCAAGA A UACGACAA 2025 TTGTCGTA GGCTAGCTACAACGA TCTTGGAA 8206
870 CCAAGAAU A CGACAACC 1091 GGTTGTCG GGCTAGCTACAACGA ATTCTTGG 8207
873 AGAAUACG A CAACCACA 2026 TGTGGTTG GGCTAGCTACAACGA CGTATTCT 8208
876 AUACGACA A CCACAUCA 2027 TGATGTGG GGCTAGCTACAACGA TGTCGTAT 8209
879 CGACAACC A CAUCAAGA 1424 TCTTGATG GGCTAGCTACAACGA GGTTGTCG 8210
881 ACAACCAC A UCAAGAGC 1425 GCTCTTGA GGCTAGCTACAACGA GTGGTTGT 8211
888 CAUCAAGA G CAGCGUGG 1851 CCACGCTG GGCTAGCTACAACGA TCTTGATG 8212
891 CAAGAGCA G CGUGGUGG 1852 CCACCACG GGCTAGCTACAACGA TGCTCTTG 8213
893 AGAGCAGC G UGGUGGGC 1853 GCCCACCA GGCTAGCTACAACGA GCTGCTCT 8214
896 GCAGCGUG G UGGGCAGU 1854 ACTGCCCA GGCTAGCTACAACGA CACGCTGC 8215
900 CGUGGUGG G CAGUGAGC 1855 GCTCACTG GGCTAGCTACAACGA CCACCACG 8216
903 GGUGGGCA G UGAGCGGA 1856 TCCGCTCA GGCTAGCTACAACGA TGCCCACC 8217
907 GGCAGUGA G CGGAAGCG 1857 CGCTTCCG GGCTAGCTACAACGA TCACTGCC 8218
913 GAGCGGAA G CGAGGAAU 1858 ATTCCTCG GGCTAGCTACAACGA TTCCGCTC 8219
920 AGCGAGGA A UGCAGCUG 2028 CAGCTGCA GGCTAGCTACAACGA TCCTCGCT 8220
922 CGAGGAAU G CAGCUGGA 1859 TCCAGCTG GGCTAGCTACAACGA ATTCCTCG 8221
925 GGAAUGCA G CUGGAAGA 1860 TCTTCCAG GGCTAGCTACAACGA TGCATTCC 8222
933 GCUGGAAG A UCUCAAAC 2029 GTTTGAGA GGCTAGCTACAACGA CTTCCAGC 8223
940 GAUCUCAA A CAGCAGCU 2030 AGCTGCTG GGCTAGCTACAACGA TTGAGATC 8224
943 CUCAAACA G CAGCUCCA 1861 TGGAGCTG GGCTAGCTACAACGA TGTTTGAG 8225
946 AAACAGCA G CUCCAGCA 1862 TGCTGGAG GGCTAGCTACAACGA TGCTGTTT 8226
952 CAGCUCCA G CAGGCCGA 1863 TCGGCCTG GGCTAGCTACAACGA TGGAGCTG 8227
956 UCCAGCAG G CCGAGGAG 1864 CTCCTCGG GGCTAGCTACAACGA CTGCTGGA 8228
965 CCGAGGAG G CCCUGGUG 1865 CACCAGGG GGCTAGCTACAACGA CTCCTCGG 8229
971 AGGCCCUG G UGGCCAAA 1866 TTTGGCCA GGCTAGCTACAACGA CAGGGCCT 8230 974 CCCUGGUG G CCAAACAG 1867 CTGTTTGG GGCTAGCTACAACGA CACCAGGG 8231
979 GUGGCCAA A CAGGAGGU 2031 ACCTCCTG GGCTAGCTACAACGA TTGGCCAC 8232
986 AACAGGAG G UGAUCGAU 1868 ATCGATCA GGCTAGCTACAACGA CTCCTGTT 8233
989 AGGAGGUG A UCGAUAAG 2032 CTTATCGA GGCTAGCTACAACGA CACCTCCT 8234
993 GGUGAUCG A UAAGCUGA 2033 TCAGCTTA GGCTAGCTACAACGA CGATCACC 8235
997 AUCGAUAA G CUGAAGGA 1869 TCCTTCAG GGCTAGCTACAACGA TTATCGAT 8236
1010 AGGAGGAG G CCGAGCAG 1870 CTGCTCGG GGCTAGCTACAACGA CTCCTCCT 8237
1015 GAGGCCGA G CAGCACAA 1871 TTGTGCTG GGCTAGCTACAACGA TCGGCCTC 8238
1018 GCCGAGCA G CACAAGAU 1872 ATCTTGTG GGCTAGCTACAACGA TGCTCGGC 8239
1020 CGAGCAGC A CAAGAUUG 1449 CAATCTTG GGCTAGCTACAACGA GCTGCTCG 8240
1025 AGCACAAG A UUGUGAUG 2034 CATCACAA GGCTAGCTACAACGA CTTGTGCT 8241
1028 ACAAGAUU G UGAUGGAG 1873 CTCCATCA GGCTAGCTACAACGA AATCTTGT 8242
1031 AGAUUGUG A UGGAGACC 2035 GGTCTCCA GGCTAGCTACAACGA CACAATCT 8243
1037 UGAUGGAG A CCGUUCCG 2036 CGGAACGG GGCTAGCTACAACGA CTCCATCA 8244
1040 UGGAGACC G UUCCGGUG 1874 CACCGGAA GGCTAGCTACAACGA GGTCTCCA 8245
1046 CCGUUCCG G UGCUGAAG 1875 CTTCAGCA GGCTAGCTACAACGA CGGAACGG 8246
1048 GUUCCGGU G CUGAAGGC 1876 GCCTTCAG GGCTAGCTACAACGA ACCGGAAC 8247
1055 UGCUGAAG G CCCAGGCG 1877 CGCCTGGG GGCTAGCTACAACGA CTTCAGCA 8248
1061 AGGCCCAG G CGGAUAUC 1878 GATATCCG GGCTAGCTACAACGA CTGGGCCT 8249
1065 CCAGGCGG A UAUCUACA 2037 TGTAGATA GGCTAGCTACAACGA CCGCCTGG 8250
1067 AGGCGGAU A UCUACAAG 1101 CTTGTAGA GGCTAGCTACAACGA ATCCGCCT 8251
1071 GGAUAUCU A CAAGGCGG 1103 CCGCCTTG GGCTAGCTACAACGA AGATATCC 8252
1076 UCUACAAG G CGGACUUC 1879 GAAGTCCG GGCTAGCTACAACGA CTTGTAGA 8253
1080 CAAGGCGG A CUUCCAGG 2038 CCTGGAAG GGCTAGCTACAACGA CCGCCTTG 8254
1088 ACUUCCAG G CUGAGAGG 1880 CCTCTCAG GGCTAGCTACAACGA CTGGAAGT 8255
1096 GCUGAGAG G CAGGCCCG 1881 CGGGCCTG GGCTAGCTACAACGA CTCTCAGC 8256
1100 AGAGGCAG G CCCGGGAG 1882 CTCCCGGG GGCTAGCTACAACGA CTGCCTCT 8257 llll CGGGAGAA G CUGGCCGA 1883 TCGGCCAG GGCTAGCTACAACGA TTCTCCCG 8258
1115 AGAAGCUG G CCGAGAAG 1884 CTTCTCGG GGCTAGCTACAACGA CAGCTTCT 8259
1129 AAGAAGGA G CUCCUGCA 1885 TGCAGGAG GGCTAGCTACAACGA TCCTTCTT 8260
1135 GAGCUCCU G CAGGAGCA 1886 TGCTCCTG GGCTAGCTACAACGA AGGAGCTC 8261
1141 CUGCAGGA G CAGCUGGA 1887 TCCAGCTG GGCTAGCTACAACGA TCCTGCAG 8262
1144 CAGGAGCA G CUGGAGCA 1888 TGCTCCAG GGCTAGCTACAACGA TGCTCCTG 8263
1150 CAGCUGGA G CAGCUGCA 1889 TGCAGCTG GGCTAGCTACAACGA TCCAGCTG 8264
1153 CUGGAGCA G CUGCAGAG 1890 CTCTGCAG GGCTAGCTACAACGA TGCTCCAG 8265
1156 GAGCAGCU G CAGAGGGA 1891 TCCCTCTG GGCTAGCTACAACGA AGCTGCTC 8266
1165 CAGAGGGA G UACAGCAA 1892 TTGCTGTA GGCTAGCTACAACGA TCCCTCTG 8267
1167 GAGGGAGU A CAGCAAAC 1107 GTTTGCTG GGCTAGCTACAACGA ACTCCCTC 8268
1170 GGAGUACA G CAAACUGA 1893 TCAGTTTG GGCTAGCTACAACGA TGTACTCC 8269
1174 UACAGCAA A CUGAAGGC 2039 GCCTTCAG GGCTAGCTACAACGA TTGCTGTA 8270
1181 AACUGAAG G CCAGCUGU 1894 ACAGCTGG GGCTAGCTACAACGA CTTCAGTT 8271
1185 GAAGGCCA G CUGUCAGG 1895 CCTGACAG GGCTAGCTACAACGA TGGCCTTC 8272
1188 GGCCAGCU G UCAGGAGU 1896 ACTCCTGA GGCTAGCTACAACGA AGCTGGCC 8273
1195 UGUCAGGA G UCGGCCAG 1897 CTGGCCGA GGCTAGCTACAACGA TCCTGACA 8274
1199 AGGAGUCG G CCAGGAUC 1898 GATCCTGG GGCTAGCTACAACGA CGACTCCT 8275
1205 CGGCCAGG A UCGAGGAC 2040 GTCCTCGA GGCTAGCTACAACGA CCTGGCCG 8276
1212 GAUCGAGG A CAUGAGGA 2041 TCCTCATG GGCTAGCTACAACGA CCTCGATC 8277
1214 UCGAGGAC A UGAGGAAG 1486 CTTCCTCA GGCTAGCTACAACGA GTCCTCGA 8278
1222 AUGAGGAA G CGGCAUGU 1899 ACATGCCG GGCTAGCTACAACGA TTCCTCAT 8279
1225 AGGAAGCG G CAUGUCGA 1900 TCGACATG GGCTAGCTACAACGA CGCTTCCT 8280
1227 GAAGCGGC A UGUCGAGG 1487 CCTCGACA GGCTAGCTACAACGA GCCGCTTC 8281 1229 AGCGGCAU G UCGAGGUC 1901 GACCTCGA GGCTAGCTACAACGA ATGCCGCT 8282
1235 AUGUCGAG G UCUCCCAG 1902 CTGGGAGA GGCTAGCTACAACGA CTCGACAT 8283
1244 UCUCCCAG G CCCCCUUG 1903 CAAGGGGG GGCTAGCTACAACGA CTGGGAGA 8284
1252 GCCCCCUU G CCCCCCGC 1904 GCGGGGGG GGCTAGCTACAACGA AAGGGGGC 8285
1259 UGCCCCCC G CCCCUGCC 1905 GGCAGGGG GGCTAGCTACAACGA GGGGGGCA 8286
1265 CCGCCCCU G CCUACCUC 1906 GAGGTAGG GGCTAGCTACAACGA AGGGGCGG 8287
1269 CCCUGCCU A CCUCUCCU 1115 AGGAGAGG GGCTAGCTACAACGA AGGCAGGG 8288
1286 CUCCCCUG G CCCUGCCC 1907 GGGCAGGG GGCTAGCTACAACGA CAGGGGAG 8289
1291 CUGGCCCU G CCCAGCCA 1908 TGGCTGGG GGCTAGCTACAACGA AGGGCCAG 8290
1296 CCUGCCCA G CCAGAGGA 1909 TCCTCTGG GGCTAGCTACAACGA TGGGCAGG 8291
1308 GAGGAGGA G CCCCCCCG 1910 CGGGGGGG GGCTAGCTACAACGA TCCTCCTC 8292
1321 CCCGAGGA G CCACCUGA 1911 TCAGGTGG GGCTAGCTACAACGA TCCTCGGG 8293
1324 GAGGAGCC A CCUGACUU 1533 AAGTCAGG GGCTAGCTACAACGA GGCTCCTC 8294
1329 GCCACCUG A CUUCUGCU 2042 AGCAGAAG GGCTAGCTACAACGA CAGGTGGC 8295
1335 UGACUUCU G CUGUCCCA 1912 TGGGACAG GGCTAGCTACAACGA AGAAGTCA 8296
1338 CUUCUGCU G UCCCAAGU 1913 ACTTGGGA GGCTAGCTACAACGA AGCAGAAG 8297
1345 UGUCCCAA G UGCCAGUA 1914 TACTGGCA GGCTAGCTACAACGA TTGGGACA 8298
1347 UCCCAAGU G CCAGUAUC 1915 GATACTGG GGCTAGCTACAACGA ACTTGGGA 8299
1351 AAGUGCCA G UAUCAGGC 1916 GCCTGATA GGCTAGCTACAACGA TGGCACTT 8300
1353 GUGCCAGU A UCAGGCCC 1123 GGGCCTGA GGCTAGCTACAACGA ACTGGCAC 8301
1358 AGUAUCAG G CCCCUGAU 1917 ATCAGGGG GGCTAGCTACAACGA CTGATACT 8302
1365 GGCCCCUG A UAUGGACA 2043 TGTCCATA GGCTAGCTACAACGA CAGGGGCC 8303
1367 CCCCUGAU A UGGACACC 1125 GGTGTCCA GGCTAGCTACAACGA ATCAGGGG 8304
1371 UGAUAUGG A CACCCUGC 2044 GCAGGGTG GGCTAGCTACAACGA CCATATCA 8305
1373 AUAUGGAC A CCCUGCAG 1549 CTGCAGGG GGCTAGCTACAACGA GTCCATAT 8306
1378 GACACCCU G CAGAUACA 1918 TGTATCTG GGCTAGCTACAACGA AGGGTGTC 8307
1382 CCCUGCAG A UACAUGUC 2045 GACATGTA GGCTAGCTACAACGA CTGCAGGG 8308
1384 CUGCAGAU A CAUGUCAU 1126 ATGACATG GGCTAGCTACAACGA ATCTGCAG 8309
1386 GCAGAUAC A UGUCAUGG 1554 CCATGACA GGCTAGCTACAACGA GTATCTGC 8310
1388 AGAUACAU G UCAUGGAG 1919 CTCCATGA GGCTAGCTACAACGA ATGTATCT 8311
1391 UACAUGUC A UGGAGUGC 1555 GCACTCCA GGCTAGCTACAACGA GACATGTA 8312
1396 GUCAUGGA G UGCAUUGA 1920 TCAATGCA GGCTAGCTACAACGA TCCATGAC 8313
1398 CAUGGAGU G CAUUGAGU 1921 ACTCAATG GGCTAGCTACAACGA ACTCCATG 8314
1400 UGGAGUGC A UUGAGUAG 1556 CTACTCAA GGCTAGCTACAACGA GCACTCCA 8315
1405 UGCAUUGA G UAGGGCCG 1922 CGGCCCTA GGCTAGCTACAACGA TCAATGCA 8316
1410 UGAGUAGG G CCGGCCAG 1923 CTGGCCGG GGCTAGCTACAACGA CCTACTCA 8317
1414 UAGGGCCG G CCAGUGCA 1924 TGCACTGG GGCTAGCTACAACGA CGGCCCTA 8318
1418 GCCGGCCA G UGCAAGGC 1925 GCCTTGCA GGCTAGCTACAACGA TGGCCGGC 8319
1420 CGGCCAGU G CAAGGCCA 1926 TGGCCTTG GGCTAGCTACAACGA ACTGGCCG 8320
1425 AGUGCAAG G CCACUGCC 1927 GGCAGTGG GGCTAGCTACAACGA CTTGCACT 8321
1428 GCAAGGCC A CUGCCUGC 1562 GCAGGCAG GGCTAGCTACAACGA GGCCTTGC 8322
1431 AGGCCACU G CCUGCCCG 1928 CGGGCAGG GGCTAGCTACAACGA AGTGGCCT 8323
1435 CACUGCCU G CCCGAGGA 1929 TCCTCGGG GGCTAGCTACAACGA AGGCAGTG 8324
1443 GCCCGAGG A CGUGCCCG 2046 CGGGCACG GGCTAGCTACAACGA CCTCGGGC 8325
1445 CCGAGGAC G UGCCCGGG 1930 CCCGGGCA GGCTAGCTACAACGA GTCCTCGG 8326
1447 GAGGACGU G CCCGGGAC 1931 GTCCCGGG GGCTAGCTACAACGA ACGTCCTC 8327
1454 UGCCCGGG A CCGUGCAG 2047 CTGCACGG GGCTAGCTACAACGA CCCGGGCA 8328
1457 CCGGGACC G UGCAGUCU 1932 AGACTGCA GGCTAGCTACAACGA GGTCCCGG 8329
1459 GGGACCGU G CAGUCUGC 1933 GCAGACTG GGCTAGCTACAACGA ACGGTCCC 8330
1462 ACCGUGCA G UCUGCGCU 1934 AGCGCAGA GGCTAGCTACAACGA TGCACGGT 8331
1466 UGCAGUCU G CGCUUUCC 1935 GGAAAGCG GGCTAGCTACAACGA AGACTGCA 8332 1468 CAGUCUGC G CUUUCCUC 1936 GAGGAAAG GGCTAGCTACAACGA GCAGACTG 8333
1481 CCUCUCCC G CCUGCCUA 1937 TAGGCAGG GGCTAGCTACAACGA GGGAGAGG 8334
1485 UCCCGCCU G CCUAGCCC 1938 GGGCTAGG GGCTAGCTACAACGA AGGCGGGA 8335
1490 CCUGCCUA G CCCAGGAU 1939 ATCCTGGG GGCTAGCTACAACGA TAGGCAGG 8336
1497 AGCCCAGG A UGAAGGGC 2048 GCCCTTCA GGCTAGCTACAACGA CCTGGGCT 8337
1504 GAUGAAGG G CUGGGUGG 1940 CCACCCAG GGCTAGCTACAACGA CCTTCATC 8338
1509 AGGGCUGG G UGGCCACA 1941 TGTGGCCA GGCTAGCTACAACGA CCAGCCCT 8339
1512 GCUGGGUG G CCACAACU 1942 AGTTGTGG GGCTAGCTACAACGA CACCCAGC 8340
1515 GGGUGGCC A CAACUGGG 1588 CCCAGTTG GGCTAGCTACAACGA GGCCACCC 8341
1518 UGGCCACA A CUGGGAUG 2049 CATCCCAG GGCTAGCTACAACGA TGTGGCCA 8342
1524 CAACUGGG A UGCCACCU 2050 AGGTGGCA GGCTAGCTACAACGA CCCAGTTG 8343
1526 ACUGGGAU G CCACCUGG 1943 CCAGGTGG GGCTAGCTACAACGA ATCCCAGT 8344
1529 GGGAUGCC A CCUGGAGC 1592 GCTCCAGG GGCTAGCTACAACGA GGCATCCC 8345
1536 CACCUGGA G CCCCACCC 1944 GGGTGGGG GGCTAGCTACAACGA TCCAGGTG 8346
1541 GGAGCCCC A CCCAGGAG 1598 CTCCTGGG GGCTAGCTACAACGA GGGGCTCC 8347
1549 ACCCAGGA G CUGGCCGC 1945 GCGGCCAG GGCTAGCTACAACGA TCCTGGGT 8348
1553 AGGAGCUG G CCGCGGCA 1946 TGCCGCGG GGCTAGCTACAACGA CAGCTCCT 8349
1556 AGCUGGCC G CGGCACCU 1947 AGGTGCCG GGCTAGCTACAACGA GGCCAGCT 8350
1559 UGGCCGCG G CACCUUAC 1948 GTAAGGTG GGCTAGCTACAACGA CGCGGCCA 8351
1561 GCCGCGGC A CCUUACGC 1604 GCGTAAGG GGCTAGCTACAACGA GCCGCGGC 8352
1566 GGCACCUU A CGCUUCAG 1138 CTGAAGCG GGCTAGCTACAACGA AAGGTGCC 8353
1568 CACCUUAC G CUUCAGCU 1949 AGCTGAAG GGCTAGCTACAACGA GTAAGGTG 8354
1574 ACGCUUCA G CUGUUGAU 1950 ATCAACAG GGCTAGCTACAACGA TGAAGCGT 8355
1577 CUUCAGCU G UUGAUCCG 1951 CGGATCAA GGCTAGCTACAACGA AGCTGAAG 8356
1581 AGCUGUUG A UCCGCUGG 2051 CCAGCGGA GGCTAGCTACAACGA CAACAGCT 8357
1585 GUUGAUCC G CUGGUCCC 1952 GGGACCAG GGCTAGCTACAACGA GGATCAAC 8358
1589 AUCCGCUG G UCCCCUCU 1953 AGAGGGGA GGCTAGCTACAACGA CAGCGGAT 8359
1604 CUUUUGGG G UAGAUGCG 1954 CGCATCTA GGCTAGCTACAACGA CCCAAAAG 8360
1608 UGGGGUAG A UGCGGCCC 2052 GGGCCGCA GGCTAGCTACAACGA CTACCCCA 8361
1610 GGGUAGAU G CGGCCCCG 1955 CGGGGCCG GGCTAGCTACAACGA ATCTACCC 8362
1613 UAGAUGCG G CCCCGAUC 1956 GATCGGGG GGCTAGCTACAACGA CGCATCTA 8363
1619 CGGCCCCG A UCAGGCCU 2053 AGGCCTGA GGCTAGCTACAACGA CGGGGCCG 8364
1624 CCGAUCAG G CCUGACUC 1957 GAGTCAGG GGCTAGCTACAACGA CTGATCGG 8365
1629 CAGGCCUG A CUCGCUGC 2054 GCAGCGAG GGCTAGCTACAACGA CAGGCCTG 8366
1633 CCUGACUC G CUGCUCUU 1958 AAGAGCAG GGCTAGCTACAACGA GAGTCAGG 8367
1636 GACUCGCU G CUCUUUUU 1959 AAAAAGAG GGCTAGCTACAACGA AGCGAGTC 8368
1645 CUCUUUUU G UUCCCUUC 1960 GAAGGGAA GGCTAGCTACAACGA AAAAAGAG 8369
1655 UCCCUUCU G UCUGCUCG 1961 CGAGCAGA GGCTAGCTACAACGA AGAAGGGA 8370
1659 UUCUGUCU G CUCGAACC 1962 GGTTCGAG GGCTAGCTACAACGA AGACAGAA 8371
1665 CUGCUCGA A CCACUUGC 2055 GCAAGTGG GGCTAGCTACAACGA TCGAGCAG 8372
1668 CUCGAACC A CUUGCCUC 1634 GAGGCAAG GGCTAGCTACAACGA GGTTCGAG 8373
1672 AACCACUU G CCUCGGGC 1963 GCCCGAGG GGCTAGCTACAACGA AAGTGGTT 8374
1679 UGCCUCGG G CUAAUCCC 1964 GGGATTAG GGCTAGCTACAACGA CCGAGGCA 8375
1683 UCGGGCUA A UCCCUCCC 2056 GGGAGGGA GGCTAGCTACAACGA TAGCCCGA 8376
1701 CUUCCUCC A CCCGGCAC 1649 GTGCCGGG GGCTAGCTACAACGA GGAGGAAG 8377
1706 UCCACCCG G CACUGGGG 1965 CCCCAGTG GGCTAGCTACAACGA CGGGTGGA 8378
1708 CACCCGGC A CUGGGGAA 1652 TTCCCCAG GGCTAGCTACAACGA GCCGGGTG 8379
1717 CUGGGGAA G UCAAGAAU 1966 ATTCTTGA GGCTAGCTACAACGA TTCCCCAG 8380
1724 AGUCAAGA A UGGGGCCU 2057 AGGCCCCA GGCTAGCTACAACGA TCTTGACT 8381
1729 AGAAUGGG G CCUGGGGC 1967 GCCCCAGG GGCTAGCTACAACGA CCCATTCT 8382
1736 GGCCUGGG G CUCUCAGG 1968 CCTGAGAG GGCTAGCTACAACGA CCCAGGCC 8383 1749 CAGGGAGA A CUGCUUCC 2058 GGAAGCAG GGCTAGCTACAACGA TCTCCCTG 8384
1752 GGAGAACU G CUUCCCCU 1969 AGGGGAAG GGCTAGCTACAACGA AGTTCTCC 8385
1762 UUCCCCUG G CAGAGCUG 1970 CAGCTCTG GGCTAGCTACAACGA CAGGGGAA 8386
1767 CUGGCAGA G CUGGGUGG 1971 CCACCCAG GGCTAGCTACAACGA TCTGCCAG 8387
1772 AGAGCUGG G UGGCAGCU 1972 AGCTGCCA GGCTAGCTACAACGA CCAGCTCT 8388
1775 GCUGGGUG G CAGCUCUU 1973 AAGAGCTG GGCTAGCTACAACGA CACCCAGC 8389
1778 GGGUGGCA G CUCUUCCU 1974 AGGAAGAG GGCTAGCTACAACGA TGCCACCC 8390
1790 UUCCUCCC A CCGGACAC 1675 GTGTCCGG GGCTAGCTACAACGA GGGAGGAA 8391
1795 CCCACCGG A CACCGACC 2059 GGTCGGTG GGCTAGCTACAACGA CCGGTGGG 8392
1797 CACCGGAC A CCGACCCG 1677 CGGGTCGG GGCTAGCTACAACGA GTCCGGTG 8393
1801 GGACACCG A CCCGCCCG 2060 CGGGCGGG GGCTAGCTACAACGA CGGTGTCC 8394
1805 ACCGACCC G CCCGCCGC 1975 GCGGCGGG GGCTAGCTACAACGA GGGTCGGT 8395
1809 ACCCGCCC G CCGCUGUG 1976 CACAGCGG GGCTAGCTACAACGA GGGCGGGT 8396
1812 CGCCCGCC G CUGUGCCC 1977 GGGCACAG GGCTAGCTACAACGA GGCGGGCG 8397
1815 CCGCCGCU G UGCCCUGG 1978 CCAGGGCA GGCTAGCTACAACGA AGCGGCGG 8398
1817 GCCGCUGU G CCCUGGGA 1979 TCCCAGGG GGCTAGCTACAACGA ACAGCGGC 8399
1826 CCCUGGGA G UGCUGCCC 1980 GGGCAGCA GGCTAGCTACAACGA TCCCAGGG 8400
1828 CUGGGAGU G CUGCCCUC 1981 GAGGGCAG GGCTAGCTACAACGA ACTCCCAG 8401
1831 GGAGUGCU G CCCUCUUA 1982 TAAGAGGG GGCTAGCTACAACGA AGCACTCC 8402
1839 GCCCUCUU A CCAUGCAC 1182 GTGCATGG GGCTAGCTACAACGA AAGAGGGC 8403
1842 CUCUUACC A UGCACACG 1694 CGTGTGCA GGCTAGCTACAACGA GGTAAGAG 8404
1844 CUUACCAU G CACACGGG 1983 CCCGTGTG GGCTAGCTACAACGA ATGGTAAG 8405
1846 UACCAUGC A CACGGGUG 1695 CACCCGTG GGCTAGCTACAACGA GCATGGTA 8406
1848 CCAUGCAC A CGGGUGCU 1696 AGCACCCG GGCTAGCTACAACGA GTGCATGG 8407
1852 GCACACGG G UGCUCUCC 1984 GGAGAGCA GGCTAGCTACAACGA CCGTGTGC 8408
1854 ACACGGGU G CUCUCCUU 1985 AAGGAGAG GGCTAGCTACAACGA ACCCGTGT 8409
1867 CCUUUUGG G CUGCAUGC 1986 GCATGCAG GGCTAGCTACAACGA CCAAAAGG 8410
1870 UUUGGGCU G CAUGCUAU 1987 ATAGCATG GGCTAGCTACAACGA AGCCCAAA 8411
1872 UGGGCUGC A UGCUAUUC 1702 GAATAGCA GGCTAGCTACAACGA GCAGCCCA 8412
1874 GGCUGCAU G CUAUUCCA 1988 TGGAATAG GGCTAGCTACAACGA ATGCAGCC 8413
1877 UGCAUGCU A UUCCAUUU 1188 AAATGGAA GGCTAGCTACAACGA AGCATGCA 8414
1882 GCUAUUCC A UUUUGCAG 1705 CTGCAAAA GGCTAGCTACAACGA GGAATAGC 8415
1887 UCCAUUUU G CAGCCAGA 1989 TCTGGCTG GGCTAGCTACAACGA AAAATGGA 8416
1890 AUUUUGCA G CCAGACCG 1990 CGGTCTGG GGCTAGCTACAACGA TGCAAAAT 8417
1895 GCAGCCAG A CCGAUGUG 2061 CACATCGG GGCTAGCTACAACGA CTGGCTGC 8418
1899 CCAGACCG A UGUGUAUU 2062 AATACACA GGCTAGCTACAACGA CGGTCTGG 8419
1901 AGACCGAU G UGUAUUUA 1991 TAAATACA GGCTAGCTACAACGA ATCGGTCT 8420
1903 ACCGAUGU G UAUUUAAC 1992 GTTAAATA GGCTAGCTACAACGA ACATCGGT 8421
1905 CGAUGUGU A UUUAACCA 1194 TGGTTAAA GGCTAGCTACAACGA ACACATCG 8422
1910 UGUAUUUA A CCAGUCAC 2063 GTGACTGG GGCTAGCTACAACGA TAAATACA 8423
1914 UUUAACCA G UCACUAUU 1993 AATAGTGA GGCTAGCTACAACGA TGGTTAAA 8424
1917 AACCAGUC A CUAUUGAU 1712 ATCAATAG GGCTAGCTACAACGA GACTGGTT 8425
1920 CAGUCACU A UUGAUGGA 1199 TCCATCAA GGCTAGCTACAACGA AGTGACTG 8426
1924 CACUAUUG A UGGACAUU 2064 AATGTCCA GGCTAGCTACAACGA CAATAGTG 8427
1928 AUUGAUGG A CAUUUGGG 2065 CCCAAATG GGCTAGCTACAACGA CCATCAAT 8428
1930 UGAUGGAC A UUUGGGUU 1714 AACCCAAA GGCTAGCTACAACGA GTCCATCA 8429
1936 ACAUUUGG G UUGUUUCC 1994 GGAAACAA GGCTAGCTACAACGA CCAAATGT 8430
1939 UUUGGGUU G UUUCCCAU 1995 ATGGGAAA GGCTAGCTACAACGA AACCCAAA 8431
1946 UGUUUCCC A UCUUUUUG 1717 CAAAAAGA GGCTAGCTACAACGA GGGAAACA 8432
1954 AUCUUUUU G UUACCAUA 1996 TATGGTAA GGCTAGCTACAACGA AAAAAGAT 8433
1957 UUUUUGUU A CCAUAAAU 1213 ATTTATGG GGCTAGCTACAACGA AACAAAAA 8434
Figure imgf000165_0001
Input Sequence = NM_003639. Cut Site = R/Y
Arm Length = 8. Core Sequence = GGCTAGCTACAACGA
NM_003639 (Homo sapiens inhibitor of kappa light polypeptide gene enhancer in B- cells, kinase gamma (IKBKG), mRNA.; 1994 bp)
Table XII: Human IKK-gamma Amberzyme and Substrate Sequence
Figure imgf000166_0001
Figure imgf000166_0002
148 CCCUGUUG G AUGAAUAG 2086 CUAUUCAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAACAGGG 8473
151 UGUUGGAU G AAUAGGCA 2087 UGCCUAUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUCCAACA 8474
156 GAUGAAUA G GCACCUCU 2088 AGAGGUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UAUUCAUC 8475
157 AUGAAUAG G CACCUCUG 1736 CAGAGGUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUAUUCAU 8476
165 GCACCUCU G GAAGAGCC 2089 GGCUCUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAGGUGC 8477
166 CACCUCUG G AAGAGCCA 2090 UGGCUCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGAGGUG 8478
Figure imgf000167_0001
169 CUCUGGAA G AGCCAACU 2091 AGUUGGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCCAGAG 8479
171 CUGGAAGA G CCAACUGU 1737 ACAGUUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUUCCAG 8480
178 AGCCAACU G UGUGAGAU 1738 AUCUCACA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGUUGGCU 8481
180 CCAACUGU G UGAGAUGG 1739 CCAUCUCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACAGUUGG 8482
182 AACUGUGU G AGAUGGUG 2092 CACCAUCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACACAGUU 8483
184 CUGUGUGA G AUGGUGCA 2093 UGCACCAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCACACAG 8484
187 UGUGAGAU G GUGCAGCC 2094 GGCUGCAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUCUCACA 8485
188 GUGAGAUG G UGCAGCCC 1740 GGGCUGCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAUCUCAC 8486
190 GAGAUGGU G CAGCCCAG 1741 CUGGGCUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACCAUCUC 8487
193 AUGGUGCA G CCCAGUGG 1742 CCACUGGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGCACCAU 8488
198 GCAGCCCA G UGGUGGCC 1743 GGCCACCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGGCUGC 8489
200 AGCCCAGU G GUGGCCCG 2095 CGGGCCAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACUGGGCU 8490
201 GCCCAGUG G UGGCCCGG 1744 CCGGGCCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CACUGGGC 8491
203 CCAGUGGU G GCCCGGCA 2096 UGCCGGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACCACUGG 8492
204 CAGUGGUG G CCCGGCAG 1745 CUGCCGGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CACCACUG 8493
208 GGUGGCCC G GCAGCAGA 2097 UCUGCUGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGGCCACC 8494
209 GUGGCCCG G CAGCAGAU 1746 AUCUGCUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGGGCCAC 8495
212 GCCCGGCA G CAGAUCAG 1747 CUGAUCUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGCCGGGC 8496
215 CGGCAGCA G AUCAGGAC 2098 GUCCUGAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGCUGCCG 8497
220 GCAGAUCA G GACGUACU 2099 AGUACGUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGAUCUGC 8498
221 CAGAUCAG G ACGUACUG 2100 CAGUACGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUGAUCUG 8499
224 AUCAGGAC G UACUGGGC 1748 GCCCAGUA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GUCCUGAU 8500
229 GACGUACU G GGCGAAGA 2101 UCUUCGCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGUACGUC 8501
230 ACGUACUG G GCGAAGAG 2102 CUCUUCGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGUACGU 8502
231 CGUACUGG G CGAAGAGU 1749 ACUCUUCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCAGUACG 8503
233 UACUGGGC G AAGAGUCU 2103 AGACUCUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCCCAGUA 8504
236 UGGGCGAA G AGUCUCCU 2104 AGGAGACU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUCGCCCA 8505
238 GGCGAAGA G UCUCCUCU 1750 AGAGGAGA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCUUCGCC 8506
247 UCUCCUCU G GGGAAGCC 2105 GGCUUCCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGAGGAGA 8507
248 CUCCUCUG G GGAAGCCA 2106 UGGCUUCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGAGGAG 8508
249 UCCUCUGG G GAAGCCAG 2107 CUGGCUUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCAGAGGA 8509
250 CCUCUGGG G AAGCCAGC 2108 GCUGGCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCAGAGG 8510
253 CUGGGGAA G CCAGCCAU 1751 AUGGCUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCCCCAG 8511
257 GGAAGCCA G CCAUGCUG 1752 CAGCAUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGCUUCC 8512
262 CCAGCCAU G CUGCACCU 1753 AGGUGCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUGGCUGG 8513
265 GCCAUGCU G CACCUGCC 1754 GGCAGGUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCAUGGC 8514
271 CUGCACCU G CCUUCAGA 1755 UCUGAAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGUGCAG 8515
Figure imgf000168_0001
278 UGCCUUCA G AACAGGGC 2109 GCCCUGUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGAAGGCA 8516
283 UCAGAACA G GGCGCUCC 2110 GGAGCGCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUUCUGA 8517
284 CAGAACAG G GCGCUCCU 2111 AGGAGCGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGUUCUG 8518
285 AGAACAGG G CGCUCCUG 1756 CAGGAGCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCUGUUCU 8519
287 AACAGGGC G CUCCUGAG 1757 CUCAGGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCCCUGUU 8520
293 GCGCUCCU G AGACCCUC 2112 GAGGGUCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGAGCGC 8521
295 GCUCCUGA G ACCCUCCA 2113 UGGAGGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCAGGAGC 8522
304 ACCCUCCA G CGCUGCCU 1758 AGGCAGCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGAGGGU 8523
306 CCUCCAGC G CUGCCUGG 1759 CCAGGCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCUGGAGG 8524
309 CCAGCGCU G CCUGGAGG 1760 CCUCCAGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCGCUGG 8525
313 CGCUGCCU G GAGGAGAA 2114 UUCUCCUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGCAGCG 8526
314 GCUGCCUG G AGGAGAAU 2115 AUUCUCCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGGCAGC 8527
316 UGCCUGGA G GAGAAUCA 2116 UGAUUCUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCAGGCA 8528
317 GCCUGGAG G AGAAUCAA 2117 UUGAUUCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUCCAGGC 8529
319 CUGGAGGA G AAUCAAGA 2118 UCUUGAUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCUCCAG 8530
326 AGAAUCAA G AGCUCCGA 2119 UCGGAGCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUGAUUCU 8531
328 AAUCAAGA G CUCCGAGA 1761 UCUCGGAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCUUGAUU 8532
333 AGAGCUCC G AGAUGCCA 2120 UGGCAUCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGAGCUCU 8533
335 AGCUCCGA G AUGCCAUC 2121 GAUGGCAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCGGAGCU 8534
338 UCCGAGAU G CCAUCCGG 1762 CCGGAUGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUCUCGGA 8535
345 UGCCAUCC G GCAGAGCA 2122 UGCUCUGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGAUGGCA 8536
346 GCCAUCCG G CAGAGCAA 1763 UUGCUCUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGGAUGGC 8537
349 AUCCGGCA G AGCAACCA 2123 UGGUUGCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGCCGGAU 8538
351 CCGGCAGA G CAACCAGA 1764 UCUGGUUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCUGCCGG 8539
358 AGCAACCA G AUUCUGCG 2124 CGCAGAAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGUUGCU 8540
364 CAGAUUCU G CGGGAGCG 1765 CGCUCCCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGAAUCUG 8541
366 GAUUCUGC G GGAGCGCU 2125 AGCGCUCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCAGAAUC 8542
367 AUUCUGCG G GAGCGCUG 2126 CAGCGCUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGCAGAAU 8543
368 UUCUGCGG G AGCGCUGC 2127 GCAGCGCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCGCAGAA 8544
370 CUGCGGGA G CGCUGCGA 1766 UCGCAGCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCCGCAG 8545
372 GCGGGAGC G CUGCGAGG 1767 CCUCGCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCUCCCGC 8546
375 GGAGCGCU G CGAGGAGC 1768 GCUCCUCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCGCUCC 8547
377 AGCGCUGC G AGGAGCUU 2128 AAGCUCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCAGCGCU 8548
379 CGCUGCGA G GAGCUUCU 2129 AGAAGCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCGCAGCG 8549
380 GCUGCGAG G AGCUUCUG 2130 CAGAAGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCGCAGC 8550
382 UGCGAGGA G CUUCUGCA 1769 UGCAGAAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCUCGCA 8551
388 GAGCUUCU G CAUUUCCA 1770 UGGAAAUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAAGCUC 8552
Figure imgf000169_0001
398 AUUUCCAA G CCAGCCAG 1771 CUGGCUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGGAAAU 8553
402 CCAAGCCA G CCAGAGGG 1772 CCCUCUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGCUUGG 8554
406 GCCAGCCA G AGGGAGGA 2131 UCCUCCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGCUGGC 8555
408 CAGCCAGA G GGAGGAGA 2132 UCUCCUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUGGCUG 8556
409 AGCCAGAG G GAGGAGAA 2133 UUCUCCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCUGGCU 8557
410 GCCAGAGG G AGGAGAAG 2134 CUUCUCCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCUCUGGC 8558
412 CAGAGGGA G GAGAAGGA 2135 uccuucuc GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCCUCUG 8559
413 AGAGGGAG G AGAAGGAG 2136 cuccuucu GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUCCCUCU 8560
415 AGGGAGGA G AAGGAGUU 2137 AACUCCUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCUCCCU 8561
418 GAGGAGAA G GAGUUCCU 2138 AGGAACUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUCUCCUC 8562
419 AGGAGAAG G AGUUCCUC 2139 GAGGAACU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUUCUCCU 8563
421 GAGAAGGA G UUCCUCAU 1773 AUGAGGAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG uccuucuc 8564
430 UUCCUCAU G UGCAAGUU 1774 AACUUGCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUGAGGAA 8565
432 CCUCAUGU G CAAGUUCC 1775 GGAACUUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACAUGAGG 8566
436 AUGUGCAA G UUCCAGGA 1776 UCCUGGAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUGCACAU 8567
442 AAGUUCCA G GAGGCCAG 2140 CUGGCCUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGAACUU 8568
443 AGUUCCAG G AGGCCAGG 2141 CCUGGCCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUGGAACU 8569
445 UUCCAGGA G GCCAGGAA 2142 UUCCUGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCUGGAA 8570
446 UCCAGGAG G CCAGGAAA 1777 UUUCCUGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUCCUGGA 8571
450 GGAGGCCA G GAAACUGG 2143 CCAGUUUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGCCUCC 8572
451 GAGGCCAG G AAACUGGU 2144 ACCAGUUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUGGCCUC 8573
457 AGGAAACU G GUGGAGAG 2145 CUCUCCAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGUUUCCU 8574
458 GGAAACUG G UGGAGAGA 1778 UCUCUCCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGUUUCC 8575
460 AAACUGGU G GAGAGACU 2146 AGUCUCUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACCAGUUU 8576
461 AACUGGUG G AGAGACUC 2147 GAGUCUCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CACCAGUU 8577
463 CUGGUGGA G AGACUCGG 2148 CCGAGUCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCACCAG 8578
465 GGUGGAGA G ACUCGGCC 2149 GGCCGAGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCUCCACC 8579
470 AGAGACUC G GCCUGGAG 2150 CUCCAGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GAGUCUCU 8580
471 GAGACUCG G CCUGGAGA 1779 UCUCCAGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGAGUCUC 8581
475 CUCGGCCU G GAGAAGCU 2151 AGCUUCUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGCCGAG 8582
476 UCGGCCUG G AGAAGCUC 2152 GAGCUUCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGGCCGA 8583
478 GGCCUGGA G AAGCUCGA 2153 UCGAGCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCAGGCC 8584
481 CUGGAGAA G CUCGAUCU 1780 AGAUCGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCUCCAG 8585
485 AGAAGCUC G AUCUGAAG 2154 CUUCAGAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GAGCUUCU 8586
490 CUCGAUCU G AAGAGGCA 2155 UGCCUCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAUCGAG 8587
493 GAUCUGAA G AGGCAGAA 2156 UUCUGCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCAGAUC 8588
495 UCUGAAGA G GCAGAAGG 2157 CCUUCUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUUCAGA 8589
Figure imgf000170_0001
496 CUGAAGAG G CAGAAGGA 1781 UCCUUCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCUUCAG 8590
499 AAGAGGCA G AAGGAGCA 2158 UGCUCCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCCUCUU 8591
502 AGGCAGAA G GAGCAGGC 2159 GCCUGCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCUGCCU 8592
503 GGCAGAAG G AGCAGGCU 2160 AGCCUGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUCUGCC 8593
505 CAGAAGGA G CAGGCUCU 1782 AGAGCCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCUUCUG 8594
508 AAGGAGCA G GCUCUGCG 2161 CGCAGAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCUCCUU 8595
509 AGGAGCAG G CUCUGCGG 1783 CCGCAGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGCUCCU 8596
514 CAGGCUCU G CGGGAGGU 1784 ACCUCCCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGAGCCUG 8597
516 GGCUCUGC G GGAGGUGG 2162 CCACCUCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCAGAGCC 8598
517 GCUCUGCG G GAGGUGGA 2163 UCCACCUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGCAGAGC 8599
518 CUCUGCGG G AGGUGGAG 2164 CUCCACCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCGCAGAG 8600
520 CUGCGGGA G GUGGAGCA 2165 UGCUCCAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCCGCAG 8601
521 UGCGGGAG G UGGAGCAC 1785 GUGCUCCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUCCCGCA 8602
523 CGGGAGGU G GAGCACCU 2166 AGGUGCUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACCUCCCG 8603
524 GGGAGGUG G AGCACCUG 2167 CAGGUGCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CACCUCCC 8604
526 GAGGUGGA G CACCUGAA 1786 UUCAGGUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCACCUC 8605
532 GAGCACCU G AAGAGAUG 2168 CAUCUCUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGUGCUC 8606
535 CACCUGAA G AGAUGCCA 2169 UGGCAUCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUCAGGUG 8607
537 CCUGAAGA G AUGCCAGC 2170 GCUGGCAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCUUCAGG 8608
540 GAAGAGAU G CCAGCAGC 1787 GCUGCUGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUCUCUUC 8609
544 AGAUGCCA G CAGCAGAU 1788 AUCUGCUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGCAUCU 8610
547 UGCCAGCA G CAGAUGGC 1789 GCCAUCUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGCUGGCA 8611
550 CAGCAGCA G AUGGCUGA 2171 UCAGCCAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGCUGCUG 8612
553 CAGCAGAU G GCUGAGGA 2172 UCCUCAGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUCUGCUG 8613
554 AGCAGAUG G CUGAGGAC 1790 GUCCUCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAUCUGCU 8614
557 AGAUGGCU G AGGACAAG 2173 CUUGUCCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCCAUCU 8615
559 AUGGCUGA G GACAAGGC 2174 GCCUUGUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCAGCCAU 8616
560 UGGCUGAG G ACAAGGCC 2175 GGCCUUGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUCAGCCA 8617
565 GAGGACAA G GCCUCUGU 2176 ACAGAGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUGUCCUC 8618
566 AGGACAAG G CCUCUGUG 1791 CACAGAGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUUGUCCU 8619
572 AGGCCUCU G UGAAAGCC 1792 GGCUUUCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGAGGCCU 8620
574 GCCUCUGU G AAAGCCCA 2177 UGGGCUUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACAGAGGC 8621
578 CUGUGAAA G CCCAGGUG 1793 CACCUGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUCACAG 8622
583 AAAGCCCA G GUGACGUC 2178 GACGUCAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGGCUUU 8623
584 AAGCCCAG G UGACGUCC 1794 GGACGUCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGGGCUU 8624
586 GCCCAGGU G ACGUCCUU 2179 AAGGACGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACCUGGGC 8625
589 CAGGUGAC G UCCUUGCU 1795 AGCAAGGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GUCACCUG 8626
Figure imgf000171_0001
595 ACGUCCUU G CUCGGGGA 1796 UCCCCGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAGGACGU 8627
599 CCUUGCUC G GGGAGCUG 2180 CAGCUCCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GAGCAAGG 8628
600 CUUGCUCG G GGAGCUGC 2181 GCAGCUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGAGCAAG 8629
601 UUGCUCGG G GAGCUGCA 2182 UGCAGCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCGAGCAA 8630
602 UGCUCGGG G AGCUGCAG 2183 CUGCAGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCGAGCA 8631
604 CUCGGGGA G CUGCAGGA 1797 UCCUGCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCCCGAG 8632
607 GGGGAGCU G CAGGAGAG 1798 CUCUCCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCUCCCC 8633
610 GAGCUGCA G GAGAGCCA 2184 UGGCUCUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGCAGCUC 8634
611 AGCUGCAG G AGAGCCAG 2185 CUGGCUCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUGCAGCU 8635
613 CUGCAGGA G AGCCAGAG 2186 CUCUGGCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCUGCAG 8636
615 GCAGGAGA G CCAGAGUC 1799 GACUCUGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCUCCUGC 8637
619 GAGAGCCA G AGUCGCUU 2187 AAGCGACU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGCUCUC 8638
621 GAGCCAGA G UCGCUUGG 1800 CCAAGCGA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCUGGCUC 8639
624 CCAGAGUC G CUUGGAGG 1801 CCUCCAAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GACUCUGG 8640
628 AGUCGCUU G GAGGCUGC 2188 GCAGCCUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAGCGACU 8641
629 GUCGCUUG G AGGCUGCC 2189 GGCAGCCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAAGCGAC 8642
631 CGCUUGGA G GCUGCCAC 2190 GUGGCAGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCAAGCG 8643
632 GCUUGGAG G CUGCCACU 1802 AGUGGCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUCCAAGC 8644
635 UGGAGGCU G CCACUAAG 1803 CUUAGUGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCCUCCA 8645
643 GCCACUAA G GAAUGCCA 2191 UGGCAUUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUAGUGGC 8646
644 CCACUAAG G AAUGCCAG 2192 CUGGCAUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUUAGUGG 8647
648 UAAGGAAU G CCAGGCUC 1804 GAGCCUGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUUCCUUA 8648
652 GAAUGCCA G GCUCUGGA 2193 UCCAGAGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGCAUUC 8649
653 AAUGCCAG G CUCUGGAG 1805 CUCCAGAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUGGCAUU 8650
658 CAGGCUCU G GAGGGUCG 2194 CGACCCUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGAGCCUG 8651
659 AGGCUCUG G AGGGUCGG 2195 CCGACCCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGAGCCU 8652
661 GCUCUGGA G GGUCGGGC 2196 GCCCGACC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCAGAGC 8653
662 CUCUGGAG G GUCGGGCC 2197 GGCCCGAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUCCAGAG 8654
663 UCUGGAGG G UCGGGCCC 1806 GGGCCCGA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCUCCAGA 8655
666 GGAGGGUC G GGCCCGGG 2198 CCCGGGCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GACCCUCC 8656
667 GAGGGUCG G GCCCGGGC 2199 GCCCGGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGACCCUC 8657
668 AGGGUCGG G CCCGGGCG 1807 CGCCCGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCGACCCU 8658
672 UCGGGCCC G GGCGGCCA 2200 UGGCCGCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGGCCCGA 8659
673 CGGGCCCG G GCGGCCAG 2201 CUGGCCGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGGGCCCG 8660
674 GGGCCCGG G CGGCCAGC 1808 GCUGGCCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCGGGCCC 8661
676 GCCCGGGC G GCCAGCGA 2202 UCGCUGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCCCGGGC 8662
677 CCCGGGCG G CCAGCGAG 1809 CUCGCUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGCCCGGG 8663
Figure imgf000172_0001
681 GGCGGCCA G CGAGCAGG 1810 CCUGCUCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGCCGCC 8664
683 CGGCCAGC G AGCAGGCG 2203 CGCCUGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCUGGCCG 8665
685 GCCAGCGA G CAGGCGCG 1811 CGCGCCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCGCUGGC 8666
688 AGCGAGCA G GCGCGGCA 2204 UGCCGCGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCUCGCU 8667
689 GCGAGCAG G CGCGGCAG 1812 CUGCCGCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGCUCGC 8668
691 GAGCAGGC G CGGCAGCU 1813 AGCUGCCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCCUGCUC 8669
693 GCAGGCGC G GCAGCUGG 2205 CCAGCUGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCGCCUGC 8670
694 CAGGCGCG G CAGCUGGA 1814 UCCAGCUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGCGCCUG 8671
697 GCGCGGCA G CUGGAGAG 1815 CUCUCCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGCCGCGC 8672
700 CGGCAGCU G GAGAGUGA 2206 UCACUCUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCUGCCG 8673
701 GGCAGCUG G AGAGUGAG 2207 CUCACUCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGCUGCC 8674
703 CAGCUGGA G AGUGAGCG 2208 CGCUCACU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCAGCUG 8675
705 GCUGGAGA G UGAGCGCG 1816 CGCGCUCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCUCCAGC 8676
707 UGGAGAGU G AGCGCGAG 2209 CUCGCGCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACUCUCCA 8677
709 GAGAGUGA G CGCGAGGC 1817 GCCUCGCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCACUCUC 8678
711 GAGUGAGC G CGAGGCGC 1818 GCGCCUCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCUCACUC 8679
713 GUGAGCGC G AGGCGCUG 2210 CAGCGCCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCGCUCAC 8680
715 GAGCGCGA G GCGCUGCA 2211 UGCAGCGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCGCGCUC 8681
716 AGCGCGAG G CGCUGCAG 1819 CUGCAGCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUCGCGCU 8682
718 CGCGAGGC G CUGCAGCA 1820 UGCUGCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCCUCGCG 8683
721 GAGGCGCU G CAGCAGCA 1821 UGCUGCUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCGCCUC 8684
724 GCGCUGCA G CAGCAGCA 1822 UGCUGCUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGCAGCGC 8685
727 CUGCAGCA G CAGCACAG 1823 CUGUGCUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGCUGCAG 8686
730 CAGCAGCA G CACAGCGU 1824 ACGCUGUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGCUGCUG 8687
735 GCAGCACA G CGUGCAGG 1825 CCUGCACG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGUGCUGC 8688
737 AGCACAGC G UGCAGGUG 1826 CACCUGCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCUGUGCU 8689
739 CACAGCGU G CAGGUGGA 1827 UCCACCUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACGCUGUG 8690
742 AGCGUGCA G GUGGACCA 2212 UGGUCCAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGCACGCU 8691
743 GCGUGCAG G UGGACCAG 1828 CUGGUCCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUGCACGC 8692
745 GUGCAGGU G GACCAGCU 2213 AGCUGGUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACCUGCAC 8693
746 UGCAGGUG G ACCAGCUG 2214 CAGCUGGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CACCUGCA 8694
751 GUGGACCA G CUGCGCAU 1829 AUGCGCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGUCCAC 8695
754 GACCAGCU G CGCAUGCA 1830 UGCAUGCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCUGGUC 8696
756 CCAGCUGC G CAUGCAGG 1831 CCUGCAUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCAGCUGG 8697
760 CUGCGCAU G CAGGGCCA 1832 UGGCCCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUGCGCAG 8698
763 CGCAUGCA G GGCCAGAG 2215 CUCUGGCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCAUGCG 8699
764 GCAUGCAG G GCCAGAGC 2216 GCUCUGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGCAUGC 8700
Figure imgf000173_0001
765 CAUGCAGG G CCAGAGCG 1833 CGCUCUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCUGCAUG 8701
769 CAGGGCCA G AGCGUGGA 2217 UCCACGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGCCCUG 8702
771 GGGCCAGA G CGUGGAGG 1834 CCUCCACG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUGGCCC 8703
773 GCCAGAGC G UGGAGGCC 1835 GGCCUCCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCUCUGGC 8704
775 CAGAGCGU G GAGGCCGC 2218 GCGGCCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACGCUCUG 8705
776 AGAGCGUG G AGGCCGCG 2219 CGCGGCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CACGCUCU 8706
778 AGCGUGGA G GCCGCGCU 2220 AGCGCGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCACGCU 8707
779 GCGUGGAG G CCGCGCUC 1836 GAGCGCGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUCCACGC 8708
782 UGGAGGCC G CGCUCCGC 1837 GCGGAGCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGCCUCCA 8709
784 GAGGCCGC G CUCCGCAU 1838 AUGCGGAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCGGCCUC 8710
789 CGCGCUCC G CAUGGAGC 1839 GCUCCAUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGAGCGCG 8711
793 CUCCGCAU G GAGCGCCA 2221 UGGCGCUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUGCGGAG 8712
794 UCCGCAUG G AGCGCCAG 2222 CUGGCGCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAUGCGGA 8713
796 CGCAUGGA G CGCCAGGC 1840 GCCUGGCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCAUGCG 8714
798 CAUGGAGC G CCAGGCCG 1841 CGGCCUGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCUCCAUG 8715
802 GAGCGCCA G GCCGCCUC 2223 GAGGCGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGCGCUC 8716
803 AGCGCCAG G CCGCCUCG 1842 CGAGGCGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUGGCGCU 8717
806 GCCAGGCC G CCUCGGAG 1843 CUCCGAGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGCCUGGC 8718
811 GCCGCCUC G GAGGAGAA 2224 UUCUCCUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GAGGCGGC 8719
812 CCGCCUCG G AGGAGAAG 2225 CUUCUCCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGAGGCGG 8720
814 GCCUCGGA G GAGAAGAG 2226 CUCUUCUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCGAGGC 8721
815 CCUCGGAG G AGAAGAGG 2227 ccucuucu GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUCCGAGG 8722
817 UCGGAGGA G AAGAGGAA 2228 UUCCUCUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCUCCGA 8723
820 GAGGAGAA G AGGAAGCU 2229 AGCUUCCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUCUCCUC 8724
822 GGAGAAGA G GAAGCUGG 2230 CCAGCUUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCUUCUCC 8725
823 GAGAAGAG G AAGCUGGC 2231 GCCAGCUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUCUUCUC 8726
826 AAGAGGAA G CUGGCCCA 1844 UGGGCCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUCCUCUU 8727
829 AGGAAGCU G GCCCAGUU 2232 AACUGGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCUUCCU 8728
830 GGAAGCUG G CCCAGUUG 1845 CAACUGGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGCUUCC 8729
835 CUGGCCCA G UUGCAGGU 1846 ACCUGCAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGGCCAG 8730
838 GCCCAGUU G CAGGUGGC 1847 GCCACCUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AACUGGGC 8731
841 CAGUUGCA G GUGGCCUA 2233 UAGGCCAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCAACUG 8732
842 AGUUGCAG G UGGCCUAU 1848 AUAGGCCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGCAACU 8733
844 UUGCAGGU G GCCUAUCA 2234 UGAUAGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACCUGCAA 8734
845 UGCAGGUG G CCUAUCAC 1849 GUGAUAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CACCUGCA 8735
856 UAUCACCA G CUCUUCCA 1850 UGGAAGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGUGAUA 8736
866 UCUUCCAA G AAUACGAC 2235 GUCGUAUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGGAAGA 8737
Figure imgf000174_0001
872 AAGAAUAC G ACAACCAC 2236 GUGGUUGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GUAUUCUU 8738
886 CACAUCAA G AGCAGCGU 2237 ACGCUGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGAUGUG 8739
888 CAUCAAGA G CAGCGUGG 1851 CCACGCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUUGAUG 8740
891 CAAGAGCA G CGUGGUGG 1852 CCACCACG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCUCUUG 8741
893 AGAGCAGC G UGGUGGGC 1853 GCCCACCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCUGCUCU 8742
895 AGCAGCGU G GUGGGCAG 2238 CUGCCCAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACGCUGCU 8743
896 GCAGCGUG G UGGGCAGU 1854 ACUGCCCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CACGCUGC 8744
898 AGCGUGGU G GGCAGUGA 2239 UCACUGCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACCACGCU 8745
899 GCGUGGUG G GCAGUGAG 2240 CUCACUGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CACCACGC 8746
900 CGUGGUGG G CAGUGAGC 1855 GCUCACUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCACCACG 8747
903 GGUGGGCA G UGAGCGGA 1856 UCCGCUCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGCCCACC 8748
905 UGGGCAGU G AGCGGAAG 2241 CUUCCGCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACUGCCCA 8749
907 GGCAGUGA G CGGAAGCG 1857 CGCUUCCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCACUGCC 8750
909 CAGUGAGC G GAAGCGAG 2242 CUCGCUUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCUCACUG 8751
910 AGUGAGCG G AAGCGAGG 2243 CCUCGCUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGCUCACU 8752
913 GAGCGGAA G CGAGGAAU 1858 AUUCCUCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUCCGCUC 8753
915 GCGGAAGC G AGGAAUGC 2244 GCAUUCCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCUUCCGC 8754
917 GGAAGCGA G GAAUGCAG 2245 CUGCAUUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCGCUUCC 8755
918 GAAGCGAG G AAUGCAGC 2246 GCUGCAUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUCGCUUC 8756
922 CGAGGAAU G CAGCUGGA 1859 UCCAGCUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUUCCUCG 8757
925 GGAAUGCA G CUGGAAGA 1860 UCUUCCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGCAUUCC 8758
928 AUGCAGCU G GAAGAUCU 2247 AGAUCUUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCUGCAU 8759
929 UGGAGCUG G AAGAUCUC 2248 GAGAUCUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGCUGCA 8760
932 AGCUGGAA G AUCUCAAA 2249 UUUGAGAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUCCAGCU 8761
943 CUCAAACA G CAGCUCCA 1861 UGGAGCUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGUUUGAG 8762
946 AAACAGCA G CUCCAGCA 1862 UGCUGGAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGCUGUUU 8763
952 CAGCUCCA G CAGGCCGA 1863 UCGGCCUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGAGCUG 8764
955 CUCCAGCA G GCCGAGGA 2250 UCCUCGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGCUGGAG 8765
956 UCCAGCAG G CCGAGGAG 1864 CUCCUCGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUGCUGGA 8766
959 AGCAGGCC G AGGAGGCC 2251 GGCCUCCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGCCUGCU 8767
961 CAGGCCGA G GAGGCCCU 2252 AGGGCCUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCGGCCUG 8768
962 AGGCCGAG G AGGCCCUG 2253 CAGGGCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCGGCCU 8769
964 GCCGAGGA G GCCCUGGU 2254 ACCAGGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCUCGGC 8770
965 CCGAGGAG G CCCUGGUG 1865 CACCAGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCCUCGG 8771
970 GAGGCCCU G GUGGCCAA 2255 UUGGCCAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGGCCUC 8772
971 AGGCCCUG G UGGCCAAA 1866 UUUGGCCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGGGCCU 8773
973 GCCCUGGU G GCCAAACA 2256 UGUUUGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACCAGGGC 8774
Figure imgf000175_0001
974 CCCUGGUG G CCAAACAG 1867 CUGUUUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CACCAGGG 8775
982 GCCAAACA G GAGGUGAU 2257 AUCACCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUUUGGC 8776
983 CCAAACAG G AGGUGAUC 2258 GAUCACCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGUUUGG 8777
985 AAACAGGA G GUGAUCGA 2259 UCGAUCAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCUGUUU 8778
986 AACAGGAG G UGAUCGAU 1868 AUCGAUCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCCUGUU 8779
988 CAGGAGGU G AUCGAUAA 2260 UUAUCGAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACCUCCUG 8780
992 AGGUGAUC G AUAAGCUG 2261 CAGCUUAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GAUCACCU 8781
997 AUCGAUAA G CUGAAGGA 1869 UCCUUCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUAUCGAU 8782
1000 GAUAAGCU G AAGGAGGA 2262 UCCUCCUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCUUAUC 8783
1003 AAGCUGAA G GAGGAGGC 2263 GCCUCCUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUCAGCUU 8784
1004 AGCUGAAG G AGGAGGCC 2264 GGCCUCCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUUCAGCU 8785
1006 CUGAAGGA G GAGGCCGA 2265 UCGGCCUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCUUCAG 8786
1007 UGAAGGAG G AGGCCGAG 2266 CUCGGCCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUCCUUCA 8787
1009 AAGGAGGA G GCCGAGCA 2267 UGCUCGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCUCCUU 8788
1010 AGGAGGAG G CCGAGCAG 1870 CUGCUCGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUCCUCCU 8789
1013 AGGAGGCC G AGCAGCAC 2268 GUGCUGCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGCCUCCU 8790
1015 GAGGCCGA G CAGCACAA 1871 UUGUGCUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCGGCCUC 8791
1018 GCCGAGCA G CACAAGAU 1872 AUCUUGUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGCUCGGC 8792
1024 CAGCACAA G AUUGUGAU 2269 AUCACAAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUGUGCUG 8793
1028 ACAAGAUU G UGAUGGAG 1873 CUCCAUCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAUCUUGU 8794
1030 AAGAUUGU G AUGGAGAC 2270 GUCUCCAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACAAUCUU 8795
1033 AUUGUGAU G GAGACCGU 2271 ACGGUCUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUCACAAU 8796
1034 UUGUGAUG G AGACCGUU 2272 AACGGUCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAUCACAA 8797
1036 GUGAUGGA G ACCGUUCC 2273 GGAACGGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCAUCAC 8798
1040 UGGAGACC G UUCCGGUG 1874 CACCGGAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGUCUCCA 8799
1045 ACCGUUCC G GUGCUGAA 2274 UUCAGCAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGAACGGU 8800
1046 CCGUUCCG G UGCUGAAG 1875 CUUCAGCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGGAACGG 8801
1048 GUUCCGGU G CUGAAGGC 1876 GCCUUCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACCGGAAC 8802
1051 CCGGUGCU G AAGGCCCA 2275 UGGGCCUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCACCGG 8803
1054 GUGCUGAA G GCCCAGGC 2276 GCCUGGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUCAGCAC 8804
1055 UGCUGAAG G CCCAGGCG 1877 CGCCUGGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUUCAGCA 8805
1060 AAGGCCCA G GCGGAUAU 2277 AUAUCCGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGGCCUU 8806
1061 AGGCCCAG G CGGAUAUC 1878 GAUAUCCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGGGCCU 8807
1063 GCCCAGGC G GAUAUCUA 2278 UAGAUAUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCCUGGGC 8808
1064 CCCAGGCG G AUAUCUAC 2279 GUAGAUAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGCCUGGG 8809
1075 AUCUACAA G GCGGACUU 2280 AAGUCCGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGUAGAU 8810
1076 UCUACAAG G CGGACUUC 1879 GAAGUCCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUGUAGA 8811
Figure imgf000176_0001
1078 UACAAGGC G GACUUCCA 2281 UGGAAGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCCUUGUA 8812
1079 ACAAGGCG G ACUUCCAG 2282 CUGGAAGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGCCUUGU 8813
1087 GACUUCCA G GCUGAGAG 2283 CUCUCAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGAAGUC 8814
1088 ACUUCCAG G CUGAGAGG 1880 CCUCUCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGGAAGU 8815
1091 UCCAGGCU G AGAGGCAG 2284 CUGCCUCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCCUGGA 8816
1093 CAGGCUGA G AGGCAGGC 2285 GCCUGCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCAGCCUG 8817
1095 GGCUGAGA G GCAGGCCC 2286 GGGCCUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUCAGCC 8818
1096 GCUGAGAG G CAGGCCCG 1881 CGGGCCUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUCUCAGC 8819
1099 GAGAGGCA G GCCCGGGA 2287 UCCCGGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGCCUCUC 8820
1100 AGAGGCAG G CCCGGGAG 1882 CUCCCGGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUGCCUCU 8821
1104 GCAGGCCC G GGAGAAGC 2288 GCUUCUCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGGCCUGC 8822
1105 CAGGCCCG G GAGAAGCU 2289 AGCUUCUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGGGCCUG 8823
1106 AGGCCCGG G AGAAGCUG 2290 CAGCUUCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCGGGCCU 8824
1108 GCCCGGGA G AAGCUGGC 2291 GCCAGCUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCCGGGC 8825 llll CGGGAGAA G CUGGCCGA 1883 UCGGCCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUCUCCCG 8826
1114 GAGAAGCU G GCCGAGAA 2292 UUCUCGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCUUCUC 8827
1115 AGAAGCUG G CCGAGAAG 1884 CUUCUCGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGCUUCU 8828
1118 AGCUGGCC G AGAAGAAG 2293 CUUCUUCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGCCAGCU 8829
1120 CUGGCCGA G AAGAAGGA 2294 UCCUUCUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCGGCCAG 8830
1123 GCCGAGAA G AAGGAGCU 2295 AGCUCCUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUCUCGGC 8831
1126 GAGAAGAA G GAGCUCCU 2296 AGGAGCUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUCUUCUC 8832
1127 AGAAGAAG G AGCUCCUG 2297 CAGGAGCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUUCUUCU 8833
1129 AAGAAGGA G CUCCUGCA 1885 UGCAGGAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCUUCUU 8834
1135 GAGCUCCU G CAGGAGCA 1886 UGCUCCUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGAGCUC 8835
1138 CUCCUGCA G GAGCAGCU 2298 AGCUGCUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGCAGGAG 8836
1139 UCCUGCAG G AGCAGCUG 2299 CAGCUGCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUGCAGGA 8837
1141 CUGCAGGA G CAGCUGGA 1887 UCCAGCUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCUGCAG 8838
1144 CAGGAGCA G CUGGAGCA 1888 UGCUCCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGCUCCUG 8839
1147 GAGCAGCU G GAGCAGCU 2300 AGCUGCUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCUGCUC 8840
1148 AGCAGCUG G AGCAGCUG 2301 CAGCUGCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGCUGCU 8841
1150 CAGCUGGA G CAGCUGCA 1889 UGGAGCUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCAGCUG 8842
1153 CUGGAGCA G CUGCAGAG 1890 CUCUGCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCUCCAG 8843
1156 GAGCAGCU G CAGAGGGA 1891 UCCCUCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCUGCUC 8844
1159 CAGCUGCA G AGGGAGUA 2302 UACUCCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCAGCUG 8845
1161 GCUGCAGA G GGAGUACA 2303 UGUACUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUGCAGC 8846
1162 CUGCAGAG G GAGUACAG 2304 CUGUACUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCUGCAG 8847
1163 UGCAGAGG G AGUACAGC 2305 GCUGUACU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCUCUGGA 8848
Figure imgf000177_0001
1165 CAGAGGGA G UACAGCAA 1892 UUGCUGUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCCUCUG 8849
1170 GGAGUACA G CAAACUGA 1893 UCAGUUUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUACUCC 8850
1177 AGCAAACU G AAGGCCAG 2306 CUGGCCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGUUUGCU 8851
1180 AAACUGAA G GCCAGCUG 2307 CAGCUGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCAGUUU 8852
1181 AACUGAAG G CCAGCUGU 1894 ACAGCUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUCAGUU 8853
1185 GAAGGCCA G CUGUCAGG 1895 CCUGACAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGCCUUC 8854
1188 GGCCAGCU G UCAGGAGU 1896 ACUCCUGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCUGGCC 8855
1192 AGCUGUCA G GAGUCGGC 2308 GCCGACUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGACAGCU 8856
1193 GCUGUCAG G AGUCGGCC 2309 GGCCGACU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUGACAGC 8857
1195 UGUCAGGA G UCGGCCAG 1897 CUGGCCGA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCUGACA 8858
1198 CAGGAGUC G GCCAGGAU 2310 AUCCUGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GACUCCUG 8859
1199 AGGAGUCG G CCAGGAUC 1898 GAUCCUGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGACUCCU 8860
1203 GUCGGCCA G GAUCGAGG 2311 CCUCGAUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGCCGAC 8861
1204 UCGGCCAG G AUCGAGGA 2312 UCCUCGAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUGGCCGA 8862
1208 CCAGGAUC G AGGACAUG 2313 CAUGUCCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GAUCCUGG 8863
1210 AGGAUCGA G GACAUGAG 2314 CUCAUGUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCGAUCCU 8864
1211 GGAUCGAG G ACAUGAGG 2315 CCUCAUGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUCGAUCC 8865
1216 GAGGACAU G AGGAAGCG 2316 CGCUUCCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUGUCCUC 8866
1218 GGACAUGA G GAAGCGGC 2317 GCCGCUUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCAUGUCC 8867
1219 GACAUGAG G AAGCGGCA 2318 UGCCGCUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUCAUGUC 8868
1222 AUGAGGAA G CGGCAUGU 1899 ACAUGCCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUCCUCAU 8869
1224 GAGGAAGC G GCAUGUCG 2319 CGACAUGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCUUCCUC 8870
1225 AGGAAGCG G CAUGUCGA 1900 UCGACAUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGCUUCCU 8871
1229 AGCGGCAU G UCGAGGUC 1901 GACCUCGA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUGCCGCU 8872
1232 GGCAUGUC G AGGUCUCC 2320 GGAGACCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GACAUGCC 8873
1234 CAUGUCGA G GUCUCCCA 2321 UGGGAGAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCGACAUG 8874
1235 AUGUCGAG G UCUCCCAG 1902 CUGGGAGA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUCGACAU 8875
1243 GUCUCCCA G GCCCCCUU 2322 AAGGGGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGGAGAC 8876
1244 UCUCCCAG G CCCCCUUG 1903 CAAGGGGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUGGGAGA 8877
1252 GCCCCCUU G CCCCCCGC 1904 GCGGGGGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAGGGGGC 8878
1259 UGCCCCCC G CCCCUGCC 1905 GGCAGGGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGGGGGCA 8879
1265 CCGCCCCU G CCUACCUC 1906 GAGGUAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGGGCGG 8880
1285 UCUCCCCU G GCCCUGCC 2323 GGCAGGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGGGAGA 8881
1286 CUCCCCUG G CCCUGCCC 1907 GGGCAGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGGGGAG 8882
1291 CUGGCCCU G CCCAGCCA 1908 UGGCUGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGGCCAG 8883
1296 CCUGCCCA G CCAGAGGA 1909 UCCUCUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGGCAGG 8884
1300 CCCAGCCA G AGGAGGAG 2324 CUCCUCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGCUGGG 8885
Figure imgf000178_0001
1302 CAGCCAGA G GAGGAGCC 2325 GGCUCCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUGGCUG 8886
1303 AGCCAGAG G AGGAGCCC 2326 GGGCUCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCUGGCU 8887
1305 CCAGAGGA G GAGCCCCC 2327 GGGGGCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCUCUGG 8888
1306 CAGAGGAG G AGCCCCCC 2328 GGGGGGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCCUCUG 8889
1308 GAGGAGGA G CCCCCCCG 1910 CGGGGGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCUCCUC 8890
1316 GCCCCCCC G AGGAGCCA 2329 UGGCUCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGGGGGGC 8891
1318 CCCCCCGA G GAGCCACC 2330 GGUGGCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCGGGGGG 8892
1319 CCCCCGAG G AGCCACCU 2331 AGGUGGCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUCGGGGG 8893
1321 CCCGAGGA G CCACCUGA 1911 UCAGGUGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCUCGGG 8894
1328 AGCCACCU G ACUUCUGC 2332 GCAGAAGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGUGGCU 8895
1335 UGACUUCU G CUGUCCCA 1912 UGGGACAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGAAGUCA 8896
1338 CUUCUGCU G UCCCAAGU 1913 ACUUGGGA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCAGAAG 8897
1345 UGUCCCAA G UGCCAGUA 1914 UACUGGCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUGGGACA 8898
1347 UCCCAAGU G CCAGUAUC 1915 GAUACUGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACUUGGGA 8899
1351 AAGUGCCA G UAUCAGGC 1916 GCCUGAUA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGCACUU 8900
1357 CAGUAUCA G GCCCCUGA 2333 UCAGGGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGAUACUG 8901
1358 AGUAUCAG G CCCCUGAU 1917 AUCAGGGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUGAUACU 8902
1364 AGGCCCCU G AUAUGGAC 2334 GUCCAUAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGGGCCU 8903
1369 CCUGAUAU G GACACCCU 2335 AGGGUGUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUAUCAGG 8904
1370 CUGAUAUG G ACACCCUG 2336 CAGGGUGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAUAUCAG 8905
1378 GACACCCU G CAGAUACA 1918 UGUAUCUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGGUGUC 8906
1381 ACCCUGCA G AUACAUGU 2337 ACAUGUAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGAGGGU 8907
1388 AGAUACAU G UCAUGGAG 1919 CUCCAUGA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUGUAUCU 8908
1393 CAUGUCAU G GAGUGCAU 2338 AUGCACUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUGACAUG 8909
1394 AUGUCAUG G AGUGCAUU 2339 AAUGCACU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAUGACAU 8910
1396 GUCAUGGA G UGCAUUGA 1920 UCAAUGCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCAUGAC 8911
1398 CAUGGAGU G CAUUGAGU 1921 ACUCAAUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACUCCAUG 8912
1403 AGUGCAUU G AGUAGGGC 2340 GCCCUACU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAUGCACU 8913
1405 UGCAUUGA G UAGGGCCG 1922 CGGCCCUA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCAAUGCA 8914
1408 AUUGAGUA G GGCCGGCC 2341 GGCCGGCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UACUCAAU 8915
1409 UUGAGUAG G GCCGGCCA 2342 UGGCCGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUACUCAA 8916
1410 UGAGUAGG G CCGGCCAG 1923 CUGGCCGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCUACUCA 8917
1413 GUAGGGCC G GCCAGUGC 2343 GCACUGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGCCCUAC 8918
1414 UAGGGCCG G CCAGUGCA 1924 UGCACUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGGCCCUA 8919
1418 GCCGGCCA G UGCAAGGC 1925 GCCUUGCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGCCGGC 8920
1420 CGGCCAGU G CAAGGCCA 1926 UGGCCUUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACUGGCCG 8921
1424 CAGUGCAA G GCCACUGC 2344 GCAGUGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGCACUG 8922
Figure imgf000179_0001
1425 AGUGCAAG G CCACUGCC 1927 GGCAGUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUGCACU 8923
1431 AGGCCACU G CCUGCCCG 1928 CGGGCAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGUGGCCU 8924
1435 CACUGCCU G CCCGAGGA 1929 UCCUCGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGCAGUG 8925
1439 GCCUGCCC G AGGACGUG 2345 CACGUCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGGCAGGC 8926
1441 CUGCCCGA G GACGUGCC 2346 GGCACGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCGGGCAG 8927
1442 UGCCCGAG G ACGUGCCC 2347 GGGCACGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCGGGCA 8928
1445 CCGAGGAC G UGCCCGGG 1930 CCCGGGCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GUCCUCGG 8929
1447 GAGGACGU G CCCGGGAC 1931 GUCCCGGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACGUCCUC 8930
1451 ACGUGCCC G GGACCGUG 2348 CACGGUCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGGCACGU 8931
1452 CGUGCCCG G GACCGUGC 2349 GCACGGUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGGGCACG 8932
1453 GUGCCCGG G ACCGUGCA 2350 UGCACGGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCGGGCAC 8933
1457 CCGGGACC G UGCAGUCU 1932 AGACUGCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGUCCCGG 8934
1459 GGGACCGU G CAGUCUGC 1933 GCAGACUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACGGUCCC 8935
1462 ACCGUGCA G UCUGCGCU 1934 AGCGCAGA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGCACGGU 8936
1466 UGCAGUCU G CGCUUUCC 1935 GGAAAGCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGACUGCA 8937
1468 CAGUCUGC G CUUUCCUC 1936 GAGGAAAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCAGACUG 8938
1481 CCUCUCCC G CCUGCCUA 1937 UAGGCAGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGGAGAGG 8939
1485 UCCCGCCU G CCUAGCCC 1938 GGGCUAGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGCGGGA 8940
1490 CCUGCCUA G CCCAGGAU 1939 AUCCUGGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UAGGCAGG 8941
1495 CUAGCCCA G GAUGAAGG 2351 CCUUCAUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGGCUAG 8942
1496 UAGCCCAG G AUGAAGGG 2352 CCCUUCAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUGGGCUA 8943
1499 CCCAGGAU G AAGGGCUG 2353 CAGCCCUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUCCUGGG 8944
1502 AGGAUGAA G GGCUGGGU 2354 ACCCAGCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUCAUCCU 8945
1503 GGAUGAAG G GCUGGGUG 2355 CACCCAGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUUCAUCC 8946
1504 GAUGAAGG G CUGGGUGG 1940 CCACCCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCUUCAUC 8947
1507 GAAGGGCU G GGUGGCCA 2356 UGGCCACC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCCCUUC 8948
1508 AAGGGCUG G GUGGCCAC 2357 GUGGCCAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGCCCUU 8949
1509 AGGGCUGG G UGGCCACA 1941 UGUGGCCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCAGCCCU 8950
1511 GGCUGGGU G GCCACAAC 2358 GUUGUGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACCCAGCC 8951
1512 GCUGGGUG G CCACAACU 1942 AGUUGUGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CACCCAGC 8952
1521 CCACAACU G GGAUGCCA 2359 UGGCAUCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGUUGUGG 8953
1522 CACAACUG G GAUGCCAC 2360 GUGGCAUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGUUGUG 8954
1523 ACAACUGG G AUGCCACC 2361 GGUGGCAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCAGUUGU 8955
1526 ACUGGGAU G CCACCUGG 1943 CCAGGUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUCCCAGU 8956
1533 UGCCACCU G GAGCCCCA 2362 UGGGGCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGUGGCA 8957
153 GCCACCUG G AGCCCCAC 2363 GUGGGGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGGUGGC 8958
1536 CACCUGGA G CCCCACCC 1944 GGGUGGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCAGGUG 8959
Figure imgf000180_0001
1546 CCCACCCA G GAGCUGGC 2364 GCCAGCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGGUGGG 8960
1547 CCACCCAG G AGCUGGCC 2365 GGCCAGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGGGUGG 8961
1549 ACCCAGGA G CUGGCCGC 1945 GCGGCCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCUGGGU 8962
1552 CAGGAGCU G GCCGCGGC 2366 GCCGCGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCUCCUG 8963
1553 AGGAGCUG G CCGCGGCA 1946 UGCCGCGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGCUCCU 8964
1556 AGCUGGCC G CGGCACCU 1947 AGGUGCCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGCCAGCU 8965
1558 CUGGCCGC G GCACCUUA 2367 UAAGGUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCGGCCAG 8966
1559 UGGCCGCG G CACCUUAC 1948 GUAAGGUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGCGGCCA 8967
1568 CACCUUAC G CUUCAGCU 1949 AGCUGAAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GUAAGGUG 8968
1574 ACGCUUCA G CUGUUGAU 1950 AUCAACAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGAAGCGU 8969
1577 CUUCAGCU G UUGAUCCG 1951 CGGAUCAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCUGAAG 8970
1580 CAGCUGUU G AUCCGCUG 2368 CAGCGGAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AACAGCUG 8971
1585 GUUGAUCC G CUGGUCCC 1952 GGGACCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGAUCAAC 8972
1588 GAUCCGCU G GUCCCCUC 2369 GAGGGGAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCGGAUC 8973
1589 AUCCGCUG G UCCCCUCU 1953 AGAGGGGA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGCGGAU 8974
1601 CCUCUUUU G GGGUAGAU 2370 AUCUACCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAAAGAGG 8975
1602 CUCUUUUG G GGUAGAUG 2371 CAUCUACC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAAAAGAG 8976
1603 UCUUUUGG G GUAGAUGC 2372 GCAUCUAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCAAAAGA 8977
1604 CUUUUGGG G UAGAUGCG 1954 CGCAUCUA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCCAAAAG 8978
1607 UUGGGGUA G AUGCGGCC 2373 GGCCGCAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UACCCCAA 8979
1610 GGGUAGAU G CGGCCCCG 1955 CGGGGCCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUCUACCC 8980
1612 GUAGAUGC G GCCCCGAU 2374 AUCGGGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCAUCUAC 8981
1613 UAGAUGCG G CCCCGAUC 1956 GAUCGGGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGCAUCUA 8982
1618 GCGGCCCC G AUCAGGCC 2375 GGCCUGAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGGGCCGC 8983
1623 CCCGAUCA G GCCUGACU 2376 AGUCAGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGAUCGGG 8984
1624 CCGAUCAG G CCUGACUC 1957 GAGUCAGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUGAUCGG 8985
1628 UCAGGCCU G ACUCGCUG 2377 CAGCGAGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGCCUGA 8986
1633 CCUGACUC G CUGCUCUU 1958 AAGAGCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GAGUCAGG 8987
1636 GACUCGCU G CUCUUUUU 1959 AAAAAGAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCGAGUC 8988
1645 CUCUUUUU G UUCCCUUC 1960 GAAGGGAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAAAAGAG 8989
1655 UCCCUUCU G UCUGCUCG 1961 CGAGCAGA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGAAGGGA 8990
1659 UUCUGUCU G CUCGAACC 1962 GGUUCGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGACAGAA 8991
1663 GUCUGCUC G AACCACUU 2378 AAGUGGUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GAGCAGAC 8992
1672 AACCACUU G CCUCGGGC 1963 GCCCGAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAGUGGUU 8993
1677 CUUGCCUC G GGCUAAUC 2379 GAUUAGCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GAGGCAAG 8994
1678 UUGCCUCG G GCUAAUCC 2380 GGAUUAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGAGGCAA 8995
1679 UGCCUCGG G CUAAUCCC 1964 GGGAUUAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCGAGGCA 8996
Figure imgf000181_0001
1705 CUCCACCC G GCACUGGG 2381 CCCAGUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGGUGGAG 8997
1706 UCCACCCG G CACUGGGG 1965 CCCCAGUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGGGUGGA 8998
1711 CCGGCACU G GGGAAGUC 2382 GACUUCCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGUGCCGG 8999
1712 CGGGACUG G GGAAGUCA 2383 UGACUUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGUGCCG 9000
1713 GGCACUGG G GAAGUCAA 2384 UUGACUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCAGUGCC 9001
1714 GCACUGGG G AAGUCAAG 2385 CUUGACUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCAGUGC 9002
1717 CUGGGGAA G UCAAGAAU 1966 AUUCUUGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCCCCAG 9003
1722 GAAGUCAA G AAUGGGGC 2386 GCCCCAUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUGACUUC 9004
1726 UCAAGAAU G GGGCCUGG 2387 CCAGGCCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUUCUUGA 9005
1727 CAAGAAUG G GGCCUGGG 2388 CCCAGGCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAUUCUUG 9006
1728 AAGAAUGG G GCCUGGGG 2389 CCCCAGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCAUUCUU 9007
1729 AGAAUGGG G CCUGGGGC 1967 GCCCCAGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCCAUUCU 9008
1733 UGGGGCCU G GGGCUCUC 2390 GAGAGCCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGCCCCA 9009
1734 GGGGCCUG G GGCUCUCA 2391 UGAGAGCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGGCCCC 9010
1735 GGGCCUGG G GCUCUCAG 2392 CUGAGAGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCAGGCCC 9011
1736 GGCCUGGG G CUCUCAGG 1968 CCUGAGAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCCAGGCC 9012
1743 GGCUCUCA G GGAGAACU 2393 AGUUCUCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGAGAGCC 9013
1744 GCUCUCAG G GAGAACUG 2394 CAGUUCUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUGAGAGC 9014
1745 CUCUCAGG G AGAACUGC 2395 GCAGUUCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCUGAGAG 9015
1747 CUCAGGGA G AACUGCUU 2396 AAGCAGUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCCUGAG 9016
1752 GGAGAACU G CUUCCCCU 1969 AGGGGAAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGUUCUCC 9017
1761 CUUCCCCU G GCAGAGCU 2397 AGCUCUGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGGGAAG 9018
1762 UUCCCCUG G CAGAGCUG 1970 CAGCUCUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGGGGAA 9019
1765 CCCUGGCA G AGCUGGGU 2398 ACCCAGCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGCCAGGG 9020
1767 CUGGCAGA G CUGGGUGG 1971 CCACCCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCUGCCAG 9021
1770 GCAGAGCU G GGUGGCAG 2399 CUGCCACC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCUCUGC 9022
1771 CAGAGCUG G GUGGCAGC 2400 GCUGCCAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGCUCUG 9023
1772 AGAGCUGG G UGGCAGCU 1972 AGCUGCCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCAGCUCU 9024
1774 AGCUGGGU G GCAGCUCU 2401 AGAGCUGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACCCAGCU 9025
1775 GCUGGGUG G CAGCUCUU 1973 AAGAGCUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CACCCAGC 9026
1778 GGGUGGCA G CUCUUCCU 1974 AGGAAGAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGCCACCC 9027
1793 CUCCCACC G GACACCGA 2402 UCGGUGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGUGGGAG 9028
1794 UCCCACCG G ACACCGAC 2403 GUCGGUGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGGUGGGA 9029
1800 CGGACACC G ACCCGCCC 2404 GGGCGGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGUGUCCG 9030
1805 ACCGACCC G CCCGCCGC 1975 GCGGCGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGGUCGGU 9031
1809 ACCCGCCC G CCGCUGUG 1976 CACAGCGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGGCGGGU 9032
1812 CGCCCGCC G CUGUGCCC 1977 GGGCACAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGCGGGCG 9033
Figure imgf000182_0001
1815 CCGCCGCU G UGCCCUGG 1978 CCAGGGCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCGGCGG 9034
1817 GCCGCUGU G CCCUGGGA 1979 UCCCAGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACAGCGGC 9035
1822 UGUGCCCU G GGAGUGCU 2405 AGCACUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGGCACA 9036
1823 GUGCCCUG G GAGUGCUG 2406 CAGCACUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGGGCAC 9037
1824 UGCCCUGG G AGUGCUGC 2407 GCAGCACU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCAGGGCA 9038
1826 CCCUGGGA G UGCUGCCC 1980 GGGCAGCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCCAGGG 9039
1828 CUGGGAGU G CUGCCCUC 1981 GAGGGCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACUCCCAG 9040
1831 GGAGUGCU G CCCUCUUA 1982 UAAGAGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCACUCC 9041
1844 CUUACCAU G CACACGGG 1983 CCCGUGUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUGGUAAG 9042
1850 AUGCACAC G GGUGCUCU 2408 AGAGCACC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GUGUGCAU 9043
1851 UGCACACG G GUGCUCUC 2409 GAGAGCAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGUGUGCA 9044
1852 GCACACGG G UGCUCUCC 1984 GGAGAGCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCGUGUGC 9045
1854 ACACGGGU G CUCUCCUU 1985 AAGGAGAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACCCGUGU 9046
1865 CUCCUUUU G GGCUGCAU 2410 AUGCAGCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAAAGGAG 9047
1866 UCCUUUUG G GCUGCAUG 2411 CAUGCAGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAAAAGGA 9048
1867 CCUUUUGG G CUGCAUGC 1986 GCAUGCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCAAAAGG 9049
1870 UUUGGGCU G CAUGCUAU 1987 AUAGCAUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCCCAAA 9050
1874 GGCUGCAU G CUAUUCCA 1988 UGGAAUAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUGCAGCC 9051
1887 UCCAUUUU G CAGCCAGA 1989 UCUGGCUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAAAUGGA 9052
1890 AUUUUGCA G CCAGACCG 1990 CGGUCUGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGCAAAAU 9053
1894 UGCAGCCA G ACCGAUGU 2412 ACAUCGGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGCUGCA 9054
1898 GCCAGACC G AUGUGUAU 2413 AUACACAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGUCUGGC 9055
1901 AGACCGAU G UGUAUUUA 1991 UAAAUACA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUCGGUCU 9056
1903 ACCGAUGU G UAUUUAAC 1992 GUUAAAUA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACAUCGGU 9057
1914 UUUAACCA G UCACUAUU 1993 AAUAGUGA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGUUAAA 9058
1923 UCACUAUU G AUGGACAU 2414 AUGUCCAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAUAGUGA 9059
1926 CUAUUGAU G GACAUUUG 2415 CAAAUGUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUCAAUAG 9060
1927 UAUUGAUG G ACAUUUGG 2416 CCAAAUGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAUCAAUA 9061
1934 GGACAUUU G GGUUGUUU 2417 AAACAACC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAAUGUCC 9062
1935 GACAUUUG G GUUGUUUC 2418 GAAACAAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAAAUGUC 9063
1936 ACAUUUGG G UUGUUUCC 1994 GGAAACAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCAAAUGU 9064
Figure imgf000183_0002
Figure imgf000183_0001
Input Sequence = NM_0O3639. Cut Site = G/ .
Arm Length = 8. Core Sequence = GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG
NM_003639 (Homo sapiens inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma (IKBKG), mRNA.; 1994 bp)
Table XIII: Human PKR Hammerhead and Substrate Sequence
Pos Substrate Seq Hammerhead Seq ID ID
20 GGCGCAGU U UGCUCAUA 2420 UAUGAGCA CUGAUGAGGCCGUUAGGCCGAA ACUGCGCC 9070
21 GCGCAGUU U GCUCAUAC 2421 GUAUGAGC CUGAUGAGGCCGUUAGGCCGAA AACUGCGC 9071
25 AGUUUGCU C AUACUUUG 2422 CAAAGUAU CUGAUGAGGCCGUUAGGCCGAA AGCAAACU 9072
28 UUGCUCAU A CUUUGUGA 2423 UCACAAAG CUGAUGAGGCCGUUAGGCCGAA AUGAGCAA 9073
31 CUCAUACU U UGUGACUU 2424 AAGUCACA CUGAUGAGGCCGUUAGGCCGAA AGUAUGAG 9074
32 UCAUACUU U GUGACUUG 2425 CAAGUCAC CUGAUGAGGCCGUUAGGCCGAA AAGUAUGA 9075
39 UUGUGACU U GCGGUCAC 2426 GUGACCGC CUGAUGAGGCCGUUAGGCCGAA AGUCACAA 9076
45 CUUGCGGU C ACAGUGGC 2427 GCCACUGU CUGAUGAGGCCGUUAGGCCGAA ACCGCAAG 9077
56 AGUGGCAU U CAGCUCCA 2428 UGGAGCUG CUGAUGAGGCCGUUAGGCCGAA AUGCCACU 9078
57 GUGGCAUU C AGCUCCAC 2429 GUGGAGCU CUGAUGAGGCCGUUAGGCCGAA AAUGCCAC 9079
62 AUUCAGCU C CACACUUG 2430 CAAGUGUG CUGAUGAGGCCGUUAGGCCGAA AGCUGAAU 9080
69 UCCACACU u GGUAGAAC 2431 GUUCUACC CUGAUGAGGCCGUUAGGCCGAA AGUGUGGA 9081
73 CACUUGGU A GAACCACA 2432 UGUGGUUC CUGAUGAGGCCGUUAGGCCGAA ACCAAGUG 9082
96 ACAAGCAU A GAAACAUC 2433 GAUGUUUC CUGAUGAGGCCGUUAGGCCGAA AUGCUUGU 9083
104 AGAAACAU C CUAAACAA 2434 UUGUUUAG CUGAUGAGGCCGUUAGGCCGAA AUGUUUCU 9084
107 AACAUCCU A AACAAUCU 2435 AGAUUGUU CUGAUGAGGCCGUUAGGCCGAA AGGAUGUU 9085
114 UAAACAAU C UUCAUCGA 2436 UCGAUGAA CUGAUGAGGCCGUUAGGCCGAA AUUGUUUA 9086
116 AACAAUCU U CAUCGAGG 2437 CCUCGAUG CUGAUGAGGCCGUUAGGCCGAA AGAUUGUU 9087
117 ACAAUCUU C AUCGAGGC 2438 GCCUCGAU CUGAUGAGGCCGUUAGGCCGAA AAGAUUGU 9088
120 AUCUUCAU C GAGGCAUC 2439 GAUGCCUC CUGAUGAGGCCGUUAGGCCGAA AUGAAGAU 9089
128 AGGCAU C GAGGUCCA 2440 UGGACCUC CUGAUGAGGCCGUUAGGCCGAA AUGCCUCG 9090
134 AUCGAGGU C CAUCCCAA 2441 UUGGGAUG CUGAUGAGGCCGUUAGGCCGAA ACCUCGAU 9091
138 AGGUCCAU C CCAAUAAA 2442 UUUAUUGG CUGAUGAGGCCGUUAGGCCGAA AUGGACCU 9092
144 AUCCCAAU A AAAAUCAG 2443 CUGAUUUU CUGAUGAGGCCGUUAGGCCGAA AUUGGGAU 9093
150 AUAAAAAU C AGGAGACC 2444 GGUCUCCU CUGAUGAGGCCGUUAGGCCGAA AUUUUUAU 9094
165 CCCUGGCU A UCAUAGAC 2445 GUCUAUGA CUGAUGAGGCCGUUAGGCCGAA AGCCAGGG 9095
167 CUGGCUAU C AUAGACCU 2446 AGGUCUAU CUGAUGAGGCCGUUAGGCCGAA AUAGCCAG 9096
170 GCUAUCAU A GACCUUAG 2447 CUAAGGUC CUGAUGAGGCCGUUAGGCCGAA AUGAUAGC 9097
176 AUAGACCU U AGUCUUCG 2448 CGAAGACU CUGAUGAGGCCGUUAGGCCGAA AGGUCUAU 9098
177 UAGACCUU A GUCUUCGC 2449 GCGAAGAC CUGAUGAGGCCGUUAGGCCGAA AAGGUCUA 9099
180 ACCUUAGU C UUCGCUGG 2450 CCAGCGAA CUGAUGAGGCCGUUAGGCCGAA ACUAAGGU 9100
182 CUUAGUCU U CGCUGGUA 2451 UACCAGCG CUGAUGAGGCCGUUAGGCCGAA AGACUAAG 9101
183 UUAGUCUU C GCUGGUAU 2452 AUACCAGC CUGAUGAGGCCGUUAGGCCGAA AAGACUAA 9102
190 UCGCUGGU A UACUCGCU 2453 AGCGAGUA CUGAUGAGGCCGUUAGGCCGAA ACCAGCGA 9103
192 GCUGGUAU A CUCGCUGU 2454 ACAGCGAG CUGAUGAGGCCGUUAGGCCGAA AUACCAGC 9104
195 GGUAUACU C GCUGUCUG 2455 CAGACAGC CUGAUGAGGCCGUUAGGCCGAA AGUAUACC 9105
201 CUCGCUGU C UGUCAACC 2456 GGUUGACA CUGAUGAGGCCGUUAGGCCGAA ACAGCGAG 9106
205 CUGUCUGU C AACCAGCG 2457 CGCUGGUU CUGAUGAGGCCGUUAGGCCGAA ACAGACAG 9107
216 CCAGCGGU U GACUUUUU 2458 AAAAAGUC CUGAUGAGGCCGUUAGGCCGAA ACCGCUGG 9108
221 GGUUGACU U UUUUUAAG 2459 CUUAAAAA CUGAUGAGGCCGUUAGGCCGAA AGUCAACC 9109
222 GUUGACUU U UUUUAAGC 2460 GCUUAAAA CUGAUGAGGCCGUUAGGCCGAA AAGUCAAC 9110
223 UUGACUUU U UUUAAGCC 2461 GGCUUAAA CUGAUGAGGCCGUUAGGCCGAA AAAGUCAA 9111
224 UGACUUUU U UUAAGCCU 2462 AGGCUUAA CUGAUGAGGCCGUUAGGCCGAA AAAAGUCA 9112
225 GACUUUUU U UAAGCCUU 2463 AAGGCUUA CUGAUGAGGCCGUUAGGCCGAA AAAAAGUC 9113
226 ACUUUUUU U AAGCCUUC 2464 GAAGGCUU CUGAUGAGGCCGUUAGGCCGAA AAAAAAGU 9114
227 CUUUUUUU A AGCCUUCU 2465 AGAAGGCU CUGAUGAGGCCGUUAGGCCGAA AAAAAAAG 9115
233 UUAAGCCU U CUUUUUUC 2466 GAAAAAAG CUGAUGAGGCCGUUAGGCCGAA AGGCUUAA 9116 234 UAAGCCUU C UUUUUUCU 2467 AGAAAAAA CUGAUGAGGCCGUUAGGCCGAA AAGGCUUA 9117
236 AGCCUUCU U uuuucucu 2468 AGAGAAAA CUGAUGAGGCCGUUAGGCCGAA AGAAGGCU 9118
237 GCCUUCUU U uuucucuu 2469 AAGAGAAA CUGAUGAGGCCGUUAGGCCGAA AAGAAGGC 9119
238 CCUUCUUU U uucucuuu 2470 AAAGAGAA CUGAUGAGGCCGUUAGGCCGAA AAAGAAGG 9120
239 CUUCUUUU U ucucuuuu 2471 AAAAGAGA CUGAUGAGGCCGUUAGGCCGAA AAAAGAAG 9121
240 UUCUUUUU U CUCUUUUA 2472 UAAAAGAG CUGAUGAGGCCGUUAGGCCGAA AAAAAGAA 9122
241 ucuuuuuu C UCUUUUAC 2473 GUAAAAGA CUGAUGAGGCCGUUAGGCCGAA AAAAAAGA 9123
243 uuuuuucu C UUUUACCA 2474 UGGUAAAA CUGAUGAGGCCGUUAGGCCGAA AGAAAAAA 9124
245 uuuucucu U UUACCAGU 2475 ACUGGUAA CUGAUGAGGCCGUUAGGCCGAA AGAGAAAA 9125
246 uuucucuu U UACCAGUU 2476 AACUGGUA CUGAUGAGGCCGUUAGGCCGAA AAGAGAAA 9126
247 uucucuuu U ACCAGUUU 2477 AAACUGGU CUGAUGAGGCCGUUAGGCCGAA AAAGAGAA 9127
248 ucucuuuu A CCAGUUUC 2478 GAAACUGG CUGAUGAGGCCGUUAGGCCGAA AAAAGAGA 9128
254 UUACCAGU U UCUGGAGC 2479 GCUCCAGA CUGAUGAGGCCGUUAGGCCGAA ACUGGUAA 9129
255 UACCAGUU U CUGGAGCA 2480 UGCUCCAG CUGAUGAGGCCGUUAGGCCGAA AACUGGUA 9130
256 ACCAGUUU C UGGAGCAA 2481 UUGCUCCA CUGAUGAGGCCGUUAGGCCGAA AAACUGGU 9131
267 GAGCAAAU U CAGUUUGC 2482 GCAAACUG CUGAUGAGGCCGUUAGGCCGAA AUUUGCUC 9132
268 AGCAAAUU C AGUUUGCC 2483 GGCAAACU CUGAUGAGGCCGUUAGGCCGAA AAUUUGCU 9133
272 AAUUCAGU U UGCCUUCC 2484 GGAAGGCA CUGAUGAGGCCGUUAGGCCGAA ACUGAAUU 9134
273 AUUCAGUU U GCCUUCCU 2485 AGGAAGGC CUGAUGAGGCCGUUAGGCCGAA AACUGAAU 9135
278 GUUUGCCU U CCUGGAUU 2486 AAUCCAGG CUGAUGAGGCCGUUAGGCCGAA AGGCAAAC 9136
279 UUUGCCUU C CUGGAUUU 2487 AAAUCCAG CUGAUGAGGCCGUUAGGCCGAA AAGGCAAA 9137
286 UCCUGGAU U UGUAAAUU 2488 AAUUUACA CUGAUGAGGCCGUUAGGCCGAA AUCCAGGA 9138
287 CCUGGAUU U GUAAAUUG 2489 CAAUUUAC CUGAUGAGGCCGUUAGGCCGAA AAUCCAGG 9139
290 GGAUUUGU A AAUUGUAA 2490 UUACAAUU CUGAUGAGGCCGUUAGGCCGAA ACAAAUCC 9140
294 UUGUAAAU U GUAAUGAC 2491 GUCAUUAC CUGAUGAGGCCGUUAGGCCGAA AUUUACAA 9141
297 UAAAUUGU A AUGACCUC 2492 GAGGUCAU CUGAUGAGGCCGUUAGGCCGAA ACAAUUUA 9142
305 AAUGACCU C AAAACUUU 2493 AAAGUUUU CUGAUGAGGCCGUUAGGCCGAA AGGUCAUU 9143
312 UCAAAACU U UAGCAGUU 2494 AACUGCUA CUGAUGAGGCCGUUAGGCCGAA AGUUUUGA 9144
313 CAAAACUU U AGCAGUUC 2495 GAACUGCU CUGAUGAGGCCGUUAGGCCGAA AAGUUUUG 9145
314 AAAACUUU A GCAGUUCU 2496 AGAACUGC CUGAUGAGGCCGUUAGGCCGAA AAAGUUUU 9146
320 UUAGCAGU U CUUCCAUC 2497 GAUGGAAG CUGAUGAGGCCGUUAGGCCGAA ACUGCUAA 9147
321 UAGCAGUU C UUCCAUCU 2498 AGAUGGAA CUGAUGAGGCCGUUAGGCCGAA AACUGCUA 9148
323 GCAGUUCU U CCAUCUGA 2499 UCAGAUGG CUGAUGAGGCCGUUAGGCCGAA AGAACUGC 9149
324 CAGUUCUU C CAUCUGAC 2500 GUCAGAUG CUGAUGAGGCCGUUAGGCCGAA AAGAACUG 9150
328 UCUUCCAU C UGACUCAG 2501 CUGAGUCA CUGAUGAGGCCGUUAGGCCGAA AUGGAAGA 9151
334 AUCUGACU C AGGUUUGC 2502 GCAAACCU CUGAUGAGGCCGUUAGGCCGAA AGUCAGAU 9152
339 ACUCAGGU U UGCUUCUC 2503 GAGAAGCA CUGAUGAGGCCGUUAGGCCGAA ACCUGAGU 9153
340 CUCAGGUU U GCUUCUCU 2504 AGAGAAGC CUGAUGAGGCCGUUAGGCCGAA AACCUGAG 9154
344 GGUUUGCU U CUCUGGCG 2505 CGCCAGAG CUGAUGAGGCCGUUAGGCCGAA AGCAAACC 9155
345 GUUUGCUU C UCUGGCGG 2506 CCGCCAGA CUGAUGAGGCCGUUAGGCCGAA AAGCAAAC 9156
347 UUGCUUCU C UGGCGGUC 2507 GACCGCCA CUGAUGAGGCCGUUAGGCCGAA AGAAGCAA 9157
355 CUGGCGGU C UUCAGAAU 2508 AUUCUGAA CUGAUGAGGCCGUUAGGCCGAA ACCGCCAG 9158
357 GGCGGUCU u CAGAAUCA 2509 UGAUUCUG CUGAUGAGGCCGUUAGGCCGAA AGACCGCC 9159
358 GCGGUCUU c AGAAUCAA 2510 UUGAUUCU CUGAUGAGGCCGUUAGGCCGAA AAGACCGC 9160
364 UUCAGAAU c AACAUCCA 2511 UGGAUGUU CUGAUGAGGCCGUUAGGCCGAA AUUCUGAA 9161
370 AUCAACAU c CACACUUC 2512 GAAGUGUG CUGAUGAGGCCGUUAGGCCGAA AUGUUGAU 9162
377 UCCACACU u CCGUGAUU 2513 AAUCACGG CUGAUGAGGCCGUUAGGCCGAA AGUGUGGA 9163
378 CCACACUU c CGUGAUUA 2514 UAAUCACG CUGAUGAGGCCGUUAGGCCGAA AAGUGUGG 9164
385 UCCGUGAU u AUCUGCGU 2515 ACGCAGAU CUGAUGAGGCCGUUAGGCCGAA AUCACGGA 9165
386 CCGUGAUU A UCUGCGUG 2516 CACGCAGA CUGAUGAGGCCGUUAGGCCGAA AAUCACGG 9166
388 GUGAUUAU C UGCGUGCA 2517 UGCACGCA CUGAUGAGGCCGUUAGGCCGAA AUAAUCAC 9167 398 GCGUGCAU U UUGGACAA 2518 UUGUCCAA CUGAUGAGGCCGUUAGGCCGAA AUGCACGC 9168
399 CGUGCAUU U UGGACAAA 2519 UUUGUCCA CUGAUGAGGCCGUUAGGCCGAA AAUGCACG 9169
400 GUGCAUUU U GGACAAAG 2520 CUUUGUCC CUGAUGAGGCCGUUAGGCCGAA AAAUGCAC 9170
411 ACAAAGCU U CCAACCAG 2521 CUGGUUGG CUGAUGAGGCCGUUAGGCCGAA AGCUUUGU 9171
412 CAAAGCUU C CAACCAGG 2522 CCUGGUUG CUGAUGAGGCCGUUAGGCCGAA AAGCUUUG 9172
423 ACCAGGAU A CGGGAAGA 2523 UCUUCCCG CUGAUGAGGCCGUUAGGCCGAA AUCCUGGU 9173
448 CUGGUGAU C UUUCAGCA 2524 UGCUGAAA CUGAUGAGGCCGUUAGGCCGAA AUCACCAG 9174
450 GGUGAUCU U UCAGCAGG 2525 CCUGCUGA CUGAUGAGGCCGUUAGGCCGAA AGAUCACC 9175
451 GUGAUCUU U CAGCAGGU 2526 ACCUGCUG CUGAUGAGGCCGUUAGGCCGAA AAGAUCAC 9176
452 UGAUCUUU C AGCAGGUU 2527 AACCUGCU CUGAUGAGGCCGUUAGGCCGAA AAAGAUCA 9177
460 CAGCAGGU U UCUUCAUG 2528 CAUGAAGA CUGAUGAGGCCGUUAGGCCGAA ACCUGCUG 9178
461 AGCAGGUU U CUUCAUGG 2529 CCAUGAAG CUGAUGAGGCCGUUAGGCCGAA AACCUGCU 9179
462 GCAGGUUU C UUCAUGGA 2530 UCCAUGAA CUGAUGAGGCCGUUAGGCCGAA AAACCUGC 9180
464 AGGUUUCU U CAUGGAGG 2531 CCUCCAUG CUGAUGAGGCCGUUAGGCCGAA AGAAACCU 9181
465 GGUUUCUU C AUGGAGGA 2532 UCCUCCAU CUGAUGAGGCCGUUAGGCCGAA AAGAAACC 9182
477 GAGGAACU U AAUACAUA 2533 UAUGUAUU CUGAUGAGGCCGUUAGGCCGAA AGUUCCUC 9183
478 AGGAACUU A AUACAUAC 2534 GUAUGUAU CUGAUGAGGCCGUUAGGCCGAA AAGUUCCU 9184
481 AACUUAAU A CAUACCGU 2535 ACGGUAUG CUGAUGAGGCCGUUAGGCCGAA AUUAAGUU 9185
485 UAAUACAU A CCGUCAGA 2536 UCUGACGG CUGAUGAGGCCGUUAGGCCGAA AUGUAUUA 9186
490 CAUACCGU C AGAAGCAG 2537 CUGCUUCU CUGAUGAGGCCGUUAGGCCGAA ACGGUAUG 9187
504 CAGGGAGU A GUACUUAA 2538 UUAAGUAC CUGAUGAGGCCGUUAGGCCGAA ACUCCCUG 9188
507 GGAGUAGU A CUUAAAUA 2539 UAUUUAAG CUGAUGAGGCCGUUAGGCCGAA ACUACUCC 9189
510 GUAGUACU U AAAUAUCA 2540 UGAUAUUU CUGAUGAGGCCGUUAGGCCGAA AGUACUAC 9190
511 UAGUACUU A AAUAUCAA 2541 UUGAUAUU CUGAUGAGGCCGUUAGGCCGAA AAGUACUA 9191
515 ACUUAAAU A UCAAGAAC 2542 GUUCUUGA CUGAUGAGGCCGUUAGGCCGAA AUUUAAGU 9192
517 UUAAAUAU C AAGAACUG 2543 CAGUUCUU CUGAUGAGGCCGUUAGGCCGAA AUAUUUAA 9193
529 AACUGCCU A AUUCAGGA 2544 UCCUGAAU CUGAUGAGGCCGUUAGGCCGAA AGGCAGUU 9194
532 UGCCUAAU U CAGGACCU 2545 AGGUCCUG CUGAUGAGGCCGUUAGGCCGAA AUUAGGCA 9195
533 GCCUAAUU C AGGACCUC 2546 GAGGUCCU CUGAUGAGGCCGUUAGGCCGAA AAUUAGGC 9196
541 CAGGACCU C CACAUGAU 2547 AUCAUGUG CUGAUGAGGCCGUUAGGCCGAA AGGUCCUG 9197
550 CACAUGAU A GGAGGUUU 2548 AAACCUCC CUGAUGAGGCCGUUAGGCCGAA AUCAUGUG 9198
557 UAGGAGGU U UACAUUUC 2549 GAAAUGUA CUGAUGAGGCCGUUAGGCCGAA ACCUCCUA 9199
558 AGGAGGUU U ACAUUUCA 2550 UGAAAUGU CUGAUGAGGCCGUUAGGCCGAA AACCUCCU 9200
559 GGAGGUUU A CAUUUCAA 2551 UUGAAAUG CUGAUGAGGCCGUUAGGCCGAA AAACCUCC 9201
563 GUUUACAU U UCAAGUUA 2552 UAACUUGA CUGAUGAGGCCGUUAGGCCGAA AUGUAAAC 9202
564 UUUACAUU U CAAGUUAU 2553 AUAACUUG CUGAUGAGGCCGUUAGGCCGAA AAUGUAAA 9203
565 UUACAUUU C AAGUUAUA 2554 UAUAACUU CUGAUGAGGCCGUUAGGCCGAA AAAUGUAA 9204
570 UUUCAAGU U AUAAUAGA 2555 UCUAUUAU CUGAUGAGGCCGUUAGGCCGAA ACUUGAAA 9205
571 UUCAAGUU A UAAUAGAU 2556 AUCUAUUA CUGAUGAGGCCGUUAGGCCGAA AACUUGAA 9206
573 CAAGUUAU A AUAGAUGG 2557 CCAUCUAU CUGAUGAGGCCGUUAGGCCGAA AUAACUUG 9207
576 GUUAUAAU A GAUGGAAG 2558 CUUCCAUC CUGAUGAGGCCGUUAGGCCGAA AUUAUAAC 9208
590 AAGAGAAU U UCCAGAAG 2559 CUUCUGGA CUGAUGAGGCCGUUAGGCCGAA AUUCUCUU 9209
591 AGAGAAUU U CCAGAAGG 2560 CCUUCUGG CUGAUGAGGCCGUUAGGCCGAA AAUUCUCU 9210
592 GAGAAUUU C CAGAAGGU 2561 ACCUUCUG CUGAUGAGGCCGUUAGGCCGAA AAAUUCUC 9211
607 GUGAAGGU A GAUCAAAG 2562 CUUUGAUC CUGAUGAGGCCGUUAGGCCGAA ACCUUCAC 9212
611 AGGUAGAU C AAAGAAGG 2563 CCUUCUUU CUGAUGAGGCCGUUAGGCCGAA AUCUACCU 9213
644 AGCCAAAU U AGCUGUUG 2564 CAACAGCU CUGAUGAGGCCGUUAGGCCGAA AUUUGGCU 9214
645 GCCAAAUU A GCUGUUGA 2565 UCAACAGC CUGAUGAGGCCGUUAGGCCGAA AAUUUGGC 9215
651 UUAGCUGU U GAGAUACU 2566 AGUAUCUC CUGAUGAGGCCGUUAGGCCGAA ACAGCUAA 9216
657 GUUGAGAU A CUUAAUAA 2567 UUAUUAAG CUGAUGAGGCCGUUAGGCCGAA AUCUCAAC 9217
660 GAGAUACU U AAUAAGGA 2568 UCCUUAUU CUGAUGAGGCCGUUAGGCCGAA AGUAUCUC 9218 661 AGAUACUU A AUAAGGAA 2569 UUCCUUAU CUGAUGAGGCCGUUAGGCCGAA AAGUAUCU 9219
664 UACUUAAU A AGGAAAAG 2570 CUUUUCCU CUGAUGAGGCCGUUAGGCCGAA AUUAAGUA 9220
681 AAGGCAGU U AGUCCUUU 2571 AAAGGACU CUGAUGAGGCCGUUAGGCCGAA ACUGCCUU 9221
682 AGGCAGUU A GUCCUUUA 2572 UAAAGGAC CUGAUGAGGCCGUUAGGCCGAA AACUGCCU 9222
685 CAGUUAGU C CUUUAUUA 2573 UAAUAAAG CUGAUGAGGCCGUUAGGCCGAA ACUAACUG 9223
688 UUAGUCCU U UAUUAUUG 2574 CAAUAAUA CUGAUGAGGCCGUUAGGCCGAA AGGACUAA 9224
689 UAGUCCUU U AUUAUUGA 2575 UCAAUAAU CUGAUGAGGCCGUUAGGCCGAA AAGGACUA 9225
690 AGUCCUUU A UUAUUGAC 2576 GUCAAUAA CUGAUGAGGCCGUUAGGCCGAA AAAGGACU 9226
692 UCCUUUAU U AUUGACAA 2577 UUGUCAAU CUGAUGAGGCCGUUAGGCCGAA AUAAAGGA 9227
693 CCUUUAUU A UUGACAAC 2578 GUUGUCAA CUGAUGAGGCCGUUAGGCCGAA AAUAAAGG 9228
695 UUUAUUAU U GACAACAA 2579 UUGUUGUC CUGAUGAGGCCGUUAGGCCGAA AUAAUAAA 9229
709 CAACGAAU U CUUCAGAA 2580 UUCUGAAG CUGAUGAGGCCGUUAGGCCGAA AUUCGUUG 9230
710 AACGAAUU C UUCAGAAG 2581 CUUCUGAA CUGAUGAGGCCGUUAGGCCGAA AAUUCGUU 9231
712 CGAAUUCU u CAGAAGGA 2582 UCCUUCUG CUGAUGAGGCCGUUAGGCCGAA AGAAUUCG 9232
713 GAAUUCUU c AGAAGGAU 2583 AUCCUUCU CUGAUGAGGCCGUUAGGCCGAA AAGAAUUC 9233
722 AGAAGGAU u AUCCAUGG 2584 CCAUGGAU CUGAUGAGGCCGUUAGGCCGAA AUCCUUCU 9234
723 GAAGGAUU A UCCAUGGG 2585 CCCAUGGA CUGAUGAGGCCGUUAGGCCGAA AAUCCUUC 9235
725 AGGAUUAU C CAUGGGGA 2586 UCCCCAUG CUGAUGAGGCCGUUAGGCCGAA AUAAUCCU 9236
736 UGGGGAAU U ACAUAGGC 2587 GCCUAUGU CUGAUGAGGCCGUUAGGCCGAA AUUCCCCA 9237
737 GGGGAAUU A CAUAGGCC 2588 GGCCUAUG CUGAUGAGGCCGUUAGGCCGAA AAUUCCCC 9238
741 AAUUACAU A GGCCUUAU 2589 AUAAGGCC CUGAUGAGGCCGUUAGGCCGAA AUGUAAUU 9239
747 AUAGGCCU U AUCAAUAG 2590 CUAUUGAU CUGAUGAGGCCGUUAGGCCGAA AGGCCUAU 9240
748 UAGGCCUU A UCAAUAGA 2591 UCUAUUGA CUGAUGAGGCCGUUAGGCCGAA AAGGCCUA 9241
750 GGCCUUAU C AAUAGAAU 2592 AUUCUAUU CUGAUGAGGCCGUUAGGCCGAA AUAAGGCC 9242
754 UUAUCAAU A GAAUUGCC 2593 GGCAAUUC CUGAUGAGGCCGUUAGGCCGAA AUUGAUAA 9243
759 AAUAGAAU U GCCCAGAA 2594 UUCUGGGC CUGAUGAGGCCGUUAGGCCGAA AUUCUAUU 9244
777 AAAAGACU A ACUGUAAA 2595 UUUACAGU CUGAUGAGGCCGUUAGGCCGAA AGUCUUUU 9245
783 CUAACUGU A AAUUAUGA 2596 UCAUAAUU CUGAUGAGGCCGUUAGGCCGAA ACAGUUAG 9246
787 CUGUAAAU U AUGAACAG 2597 CUGUUCAU CUGAUGAGGCCGUUAGGCCGAA AUUUACAG 9247
788 UGUAAAUU A UGAACAGU 2598 ACUGUUCA CUGAUGAGGCCGUUAGGCCGAA AAUUUACA 9248
803 GUGUGCAU C GGGGGUGC 2599 GCACCCCC CUGAUGAGGCCGUUAGGCCGAA AUGCACAC 9249
827 AGAAGGAU U UCAUUAUA 2600 UAUAAUGA CUGAUGAGGCCGUUAGGCCGAA AUCCUUCU 9250
828 GAAGGAUU U CAUUAUAA 2601 UUAUAAUG CUGAUGAGGCCGUUAGGCCGAA AAUCCUUC 9251
829 AAGGAUUU C AUUAUAAA 2602 UUUAUAAU CUGAUGAGGCCGUUAGGCCGAA AAAUCCUU 9252
832 GAUUUCAU U AUAAAUGC 2603 GCAUUUAU CUGAUGAGGCCGUUAGGCCGAA AUGAAAUC 9253
833 AUUUCAUU A UAAAUGCA 2604 UGCAUUUA CUGAUGAGGCCGUUAGGCCGAA AAUGAAAU 9254
835 UUCAUUAU A AAUGCAAA 2605 UUUGCAUU CUGAUGAGGCCGUUAGGCCGAA AUAAUGAA 9255
860 GAAAGAAU A UAGUAUUG 2606 CAAUACUA CUGAUGAGGCCGUUAGGCCGAA AUUCUUUC 9256
862 AAGAAUAU A GUAUUGGU 2607 ACCAAUAC CUGAUGAGGCCGUUAGGCCGAA AUAUUCUU 9257
865 AAUAUAGU A UUGGUACA 2608 UGUACCAA CUGAUGAGGCCGUUAGGCCGAA ACUAUAUU 9258
867 UAUAGUAU U GGUACAGG 2609 CCUGUACC CUGAUGAGGCCGUUAGGCCGAA AUACUAUA 9259
871 GUAUUGGU A CAGGUUCU 2610 AGAACCUG CUGAUGAGGCCGUUAGGCCGAA ACCAAUAC 9260
877 GUACAGGU U CUACUAAA 2611 UUUAGUAG CUGAUGAGGCCGUUAGGCCGAA ACCUGUAC 9261
878 UACAGGUU C UACUAAAC 2612 GUUUAGUA CUGAUGAGGCCGUUAGGCCGAA AACCUGUA 9262
880 CAGGUUCU A CUAAACAG 2613 CUGUUUAG CUGAUGAGGCCGUUAGGCCGAA AGAACCUG 9263
883 GUUCUACU A AACAGGAA 2614 UUCCUGUU CUGAUGAGGCCGUUAGGCCGAA AGUAGAAC 9264
902 AAAACAAU U GGCCGCUA 2615 UAGCGGCC CUGAUGAGGCCGUUAGGCCGAA AUUGUUUU 9265
910 UGGCCGCU A AACUUGCA 2616 UGCAAGUU CUGAUGAGGCCGUUAGGCCGAA AGCGGCCA 9266
915 GCUAAACU U GCAUAUCU 2617 AGAUAUGC CUGAUGAGGCCGUUAGGCCGAA AGUUUAGC 9267
920 ACUUGCAU A UCUUCAGA 2618 UCUGAAGA CUGAUGAGGCCGUUAGGCCGAA AUGCAAGU 9268
922 UUGCAUAU C UUCAGAUA 2619 UAUCUGAA CUGAUGAGGCCGUUAGGCCGAA AUAUGCAA 9269 924 GCAUAUCU U CAGAUAUU 2620 AAUAUCUG CUGAUGAGGCCGUUAGGCCGAA AGAUAUGC 9270
925 CAUAUCUU C AGAUAUUA 2621 UAAUAUCU CUGAUGAGGCCGUUAGGCCGAA AAGAUAUG 9271
930 CUUCAGAU A UUAUCAGA 2622 UCUGAUAA CUGAUGAGGCCGUUAGGCCGAA AUCUGAAG 9272
932 UCAGAUAU U AUCAGAAG 2623 CUUCUGAU CUGAUGAGGCCGUUAGGCCGAA AUAUCUGA 9273
933 CAGAUAUU A UCAGAAGA 2624 UCUUCUGA CUGAUGAGGCCGUUAGGCCGAA AAUAUCUG 9274
935 GAUAUUAU C AGAAGAAA 2625 UUUCUUCU CUGAUGAGGCCGUUAGGCCGAA AUAAUAUC 9275
947 AGAAACCU C AGUGAAAU 2626 AUUUCACU CUGAUGAGGCCGUUAGGCCGAA AGGUUUCU 9276
956 AGUGAAAU C UGACUACC 2627 GGUAGUCA CUGAUGAGGCCGUUAGGCCGAA AUUUCACU 9277
962 AUCUGACU A CCUGUCCU 2628 AGGACAGG CUGAUGAGGCCGUUAGGCCGAA AGUCAGAU 9278
968 CUACCUGU C CUCUGGUU 2629 AACCAGAG CUGAUGAGGCCGUUAGGCCGAA ACAGGUAG 9279
971 CCUGUCCU C UGGUUCUU 2630 AAGAACCA CUGAUGAGGCCGUUAGGCCGAA AGGACAGG 9280
976 CCUCUGGU U CUUUUGCU 2631 AGCAAAAG CUGAUGAGGCCGUUAGGCCGAA ACCAGAGG 9281
977 CUCUGGUU C UUUUGCUA 2632 UAGCAAAA CUGAUGAGGCCGUUAGGCCGAA AACCAGAG 9282
979 CUGGUUCU U UUGCUACU 2633 AGUAGCAA CUGAUGAGGCCGUUAGGCCGAA AGAACCAG 9283
980 UGGUUCUU U UGCUACUA 2634 UAGUAGCA CUGAUGAGGCCGUUAGGCCGAA AAGAACCA 9284
981 GGUUCUUU U GCUACUAC 2635 GUAGUAGC CUGAUGAGGCCGUUAGGCCGAA AAAGAACC 9285
985 CUUUUGCU A CUACGUGU 2636 ACACGUAG CUGAUGAGGCCGUUAGGCCGAA AGCAAAAG 9286
988 UUGCUACU A CGUGUGAG 2637 CUCACACG CUGAUGAGGCCGUUAGGCCGAA AGUAGCAA 9287
998 GUGUGAGU C CCAAAGCA 2638 UGCUUUGG CUGAUGAGGCCGUUAGGCCGAA ACUCACAC 9288
1010 AAGCAACU C UUUAGUGA 2639 UCACUAAA CUGAUGAGGCCGUUAGGCCGAA AGUUGCUU 9289
1012 GCAACUCU U UAGUGACC 2640 GGUCACUA CUGAUGAGGCCGUUAGGCCGAA AGAGUUGC 9290
1013 CAACUCUU U AGUGACCA 2641 UGGUCACU CUGAUGAGGCCGUUAGGCCGAA AAGAGUUG 9291
1014 AACUCUUU A GUGACCAG 2642 CUGGUCAC CUGAUGAGGCCGUUAGGCCGAA AAAGAGUU 9292
1029 AGCACACU C GCUUCUGA 2643 UCAGAAGC CUGAUGAGGCCGUUAGGCCGAA AGUGUGCU 9293
1033 CACUCGCU U CUGAAUCA 2644 UGAUUCAG CUGAUGAGGCCGUUAGGCCGAA AGCGAGUG 9294
1034 ACUCGCUU C UGAAUCAU 2645 AUGAUUCA CUGAUGAGGCCGUUAGGCCGAA AAGCGAGU 9295
1040 UUCUGAAU C AUCAUCUG 2646 CAGAUGAU CUGAUGAGGCCGUUAGGCCGAA AUUCAGAA 9296
1043 UGAAUCAU C AUCUGAAG 2647 CUUCAGAU CUGAUGAGGCCGUUAGGCCGAA AUGAUUCA 9297
1046 AUCAUCAU C UGAAGGUG 2648 CACCUUCA CUGAUGAGGCCGUUAGGCCGAA AUGAUGAU 9298
1058 AGGUGACU U CUCAGCAG 2649 CUGCUGAG CUGAUGAGGCCGUUAGGCCGAA AGUCACCU 9299
1059 GGUGACUU C UCAGCAGA 2650 UCUGCUGA CUGAUGAGGCCGUUAGGCCGAA AAGUCACC 9300
1061 UGACUUCU C AGCAGAUA 2651 UAUCUGCU CUGAUGAGGCCGUUAGGCCGAA AGAAGUCA 9301
1069 CAGCAGAU A CAUCAGAG 2652 CUCUGAUG CUGAUGAGGCCGUUAGGCCGAA AUCUGCUG 9302
1073 AGAUACAU C AGAGAUAA 2653 UUAUCUCU CUGAUGAGGCCGUUAGGCCGAA AUGUAUCU 9303
1080 UCAGAGAU A AAUUCUAA 2654 UUAGAAUU CUGAUGAGGCCGUUAGGCCGAA AUCUCUGA 9304
1084 AGAUAAAU U CUAACAGU 2655 ACUGUUAG CUGAUGAGGCCGUUAGGCCGAA AUUUAUCU 9305
1085 GAUAAAUU C UAACAGUG 2656 CACUGUUA CUGAUGAGGCCGUUAGGCCGAA AAUUUAUC 9306
1087 UAAAUUCU A ACAGUGAC 2657 GUCACUGU CUGAUGAGGCCGUUAGGCCGAA AGAAUUUA 9307
1099 GUGACAGU U UAAACAGU 2658 ACUGUUUA CUGAUGAGGCCGUUAGGCCGAA ACUGUCAC 9308
1100 UGACAGUU U AAACAGUU 2659 AACUGUUU CUGAUGAGGCCGUUAGGCCGAA AACUGUCA 9309
1101 GACAGUUU A AACAGUUC 2660 GAACUGUU CUGAUGAGGCCGUUAGGCCGAA AAACUGUC 9310
1108 UAAACAGU U CUUCGUUG 2661 CAACGAAG CUGAUGAGGCCGUUAGGCCGAA ACUGUUUA 9311
1109 AAACAGUU C UUCGUUGC 2662 GCAACGAA CUGAUGAGGCCGUUAGGCCGAA AACUGUUU 9312 llll ACAGUUCU U CGUUGCUU 2663 AAGCAACG CUGAUGAGGCCGUUAGGCCGAA AGAACUGU 9313
1112 CAGUUCUU C GUUGCUUA 2664 UAAGCAAC CUGAUGAGGCCGUUAGGCCGAA AAGAACUG 9314
1115 UUCUUCGU U GCUUAUGA 2665 UCAUAAGC CUGAUGAGGCCGUUAGGCCGAA ACGAAGAA 9315
1119 UCGUUGCU U AUGAAUGG 2666 CCAUUCAU CUGAUGAGGCCGUUAGGCCGAA AGCAACGA 9316
1120 CGUUGCUU A UGAAUGGU 2667 ACCAUUCA CUGAUGAGGCCGUUAGGCCGAA AAGCAACG 9317
1129 UGAAUGGU C UCAGAAAU 2668 AUUUCUGA CUGAUGAGGCCGUUAGGCCGAA ACCAUUCA 9318
1131 AAUGGUCU C AGAAAUAA 2669 UUAUUUCU CUGAUGAGGCCGUUAGGCCGAA AGACCAUU 9319
1138 UCAGAAAU A AUCAAAGG 2670 CCUUUGAU CUGAUGAGGCCGUUAGGCCGAA AUUUCUGA 9320 1141 GAAAUAAU C AAAGGAAG 2671 CUUCCUUU CUGAUGAGGCCGUUAGGCCGAA AUUAUUUC 9321
1160 AAAAAGAU C UUUGGCAC 2672 GUGCCAAA CUGAUGAGGCCGUUAGGCCGAA AUCUUUUU 9322
1162 AAAGAUCU U UGGCACCC 2673 GGGUGCCA CUGAUGAGGCCGUUAGGCCGAA AGAUCUUU 9323
1163 AAGAUCUU U GGCACCCA 2674 UGGGUGCC CUGAUGAGGCCGUUAGGCCGAA AAGAUCUU 9324
1175 ACCCAGAU U UGACCUUC 2675 GAAGGUCA CUGAUGAGGCCGUUAGGCCGAA AUCUGGGU 9325
1176 CCCAGAUU U GACCUUCC 2676 GGAAGGUC CUGAUGAGGCCGUUAGGCCGAA AAUCUGGG 9326
1182 UUUGACCU U CCUGACAU 2677 AUGUCAGG CUGAUGAGGCCGUUAGGCCGAA AGGUCAAA 9327
1183 UUGACCUU C CUGACAUG 2678 CAUGUCAG CUGAUGAGGCCGUUAGGCCGAA AAGGUCAA 9328
1205 AACAAAGU A UACUGUGG 2679 CCACAGUA CUGAUGAGGCCGUUAGGCCGAA ACUUUGUU 9329
1207 CAAAGUAU A CUGUGGAC 2680 GUCCACAG CUGAUGAGGCCGUUAGGCCGAA AUACUUUG 9330
1223 CAAGAGGU U UGGCAUGG 2681 CCAUGCCA CUGAUGAGGCCGUUAGGCCGAA ACCUCUUG 9331
1224 AAGAGGUU U GGCAUGGA 2682 UCCAUGCC CUGAUGAGGCCGUUAGGCCGAA AACCUCUU 9332
1234 GCAUGGAU U UUAAAGAA 2683 UUCUUUAA CUGAUGAGGCCGUUAGGCCGAA AUCCAUGC 9333
1235 CAUGGAUU U UAAAGAAA 2684 UUUCUUUA CUGAUGAGGCCGUUAGGCCGAA AAUCCAUG 9334
1236 AUGGAUUU U AAAGAAAU 2685 AUUUCUUU CUGAUGAGGCCGUUAGGCCGAA AAAUCCAU 9335
1237 UGGAUUUU A AAGAAAUA 2686 UAUUUCUU CUGAUGAGGCCGUUAGGCCGAA AAAAUCCA 9336
1245 AAAGAAAU A GAAUUAAU 2687 AUUAAUUC CUGAUGAGGCCGUUAGGCCGAA AUUUCUUU 9337
1250 AAUAGAAU U AAUUGGCU 2688 AGCCAAUU CUGAUGAGGCCGUUAGGCCGAA AUUCUAUU 9338
1251 AUAGAAUU A AUUGGCUC 2689 GAGCCAAU CUGAUGAGGCCGUUAGGCCGAA AAUUCUAU 9339
1254 GAAUUAAU U GGCUCAGG 2690 CCUGAGCC CUGAUGAGGCCGUUAGGCCGAA AUUAAUUC 9340
1259 AAUUGGCU C AGGUGGAU 2691 AUCCACCU CUGAUGAGGCCGUUAGGCCGAA AGCCAAUU 9341
1268 AGGUGGAU U UGGCCAAG 2692 CUUGGCCA CUGAUGAGGCCGUUAGGCCGAA AUCCACCU 9342
1269 GGUGGAUU U GGCCAAGU 2693 ACUUGGCC CUGAUGAGGCCGUUAGGCCGAA AAUCCACC 9343
1278 GGCCAAGU U UUCAAAGC 2694 GCUUUGAA CUGAUGAGGCCGUUAGGCCGAA ACUUGGCC 9344
1279 GCCAAGUU u UCAAAGCA 2695 UGCUUUGA CUGAUGAGGCCGUUAGGCCGAA AACUUGGC 9345
1280 CCAAGUUU u CAAAGCAA 2696 UUGCUUUG CUGAUGAGGCCGUUAGGCCGAA AAACUUGG 9346
1281 CAAGUUUU c AAAGCAAA 2697 UUUGCUUU CUGAUGAGGCCGUUAGGCCGAA AAAACUUG 9347
1299 CACAGAAU u GACGGAAA 2698 UUUCCGUC CUGAUGAGGCCGUUAGGCCGAA AUUCUGUG 9348
1312 GAAAGACU u ACGUUAUU 2699 AAUAACGU CUGAUGAGGCCGUUAGGCCGAA AGUCUUUC 9349
1313 AAAGACUU A CGUUAUUA 2700 UAAUAACG CUGAUGAGGCCGUUAGGCCGAA AAGUCUUU 9350
1317 ACUUACGU U AUUAAACG 2701 CGUUUAAU CUGAUGAGGCCGUUAGGCCGAA ACGUAAGU 9351
1318 CUUACGUU A UUAAACGU 2702 ACGUUUAA CUGAUGAGGCCGUUAGGCCGAA AACGUAAG 9352
1320 UACGUUAU U AAACGUGU 2703 ACACGUUU CUGAUGAGGCCGUUAGGCCGAA AUAACGUA 9353
1321 ACGUUAUU A AACGUGUU 2704 AACACGUU CUGAUGAGGCCGUUAGGCCGAA AAUAACGU 9354
1329 AAACGUGU u AAAUAUAA 2705 UUAUAUUU CUGAUGAGGCCGUUAGGCCGAA ACACGUUU 9355
1330 AACGUGUU A AAUAUAAU 2706 AUUAUAUU CUGAUGAGGCCGUUAGGCCGAA AACACGUU 9356
1334 UGUUAAAU A UAAUAACG 2707 CGUUAUUA CUGAUGAGGCCGUUAGGCCGAA AUUUAACA 9357
1336 UUAAAUAU A AUAACGAG 2708 CUCGUUAU CUGAUGAGGCCGUUAGGCCGAA AUAUUUAA 9358
1339 AAUAUAAU A ACGAGAAG 2709 CUUCUCGU CUGAUGAGGCCGUUAGGCCGAA AUUAUAUU 9359
1362 CGUGAAGU A AAAGCAUU 2710 AAUGCUUU CUGAUGAGGCCGUUAGGCCGAA ACUUCACG 9360
1370 AAAAGCAU U GGCAAAAC 2711 GUUUUGCC CUGAUGAGGCCGUUAGGCCGAA AUGCUUUU 9361
1380 GCAAAACU U GAUCAUGU 2712 ACAUGAUC CUGAUGAGGCCGUUAGGCCGAA AGUUUUGC 9362
1384 AACUUGAU C AUGUAAAU 2713 AUUUACAU CUGAUGAGGCCGUUAGGCCGAA AUCAAGUU 9363
1389 GAUCAUGU A AAUAUUGU 2714 ACAAUAUU CUGAUGAGGCCGUUAGGCCGAA ACAUGAUC 9364
1393 AUGUAAAU A UUGUUCAC 2715 GUGAACAA CUGAUGAGGCCGUUAGGCCGAA AUUUACAU 9365
1395 GUAAAUAU U GUUCACUA 2716 UAGUGAAC CUGAUGAGGCCGUUAGGCCGAA AUAUUUAC 9366
1398 AAUAUUGU U CACUACAA 2717 UUGUAGUG CUGAUGAGGCCGUUAGGCCGAA ACAAUAUU 9367
1399 AUAUUGUU C ACUACAAU 2718 AUUGUAGU CUGAUGAGGCCGUUAGGCCGAA AACAAUAU 9368
1403 UGUUCACU A CAAUGGCU 2719 AGCCAUUG CUGAUGAGGCCGUUAGGCCGAA AGUGAACA 9369
1414 AUGGCUGU U GGGAUGGA 2720 UCCAUCCC CUGAUGAGGCCGUUAGGCCGAA ACAGCCAU 9370
1424 GGAUGGAU U UGAUUAUG 2721 CAUAAUCA CUGAUGAGGCCGUUAGGCCGAA AUCCAUCC 9371 1425 GAUGGAUU U GAUUAUGA 2722 UCAUAAUC CUGAUGAGGCCGUUAGGCCGAA AAUCCAUC 9372
1429 GAUUUGAU U AUGAUCCU 2723 AGGAUCAU CUGAUGAGGCCGUUAGGCCGAA AUCAAAUC 9373
1430 AUUUGAUU A UGAUCCUG 2724 CAGGAUCA CUGAUGAGGCCGUUAGGCCGAA AAUCAAAU 937
1435 AUUAUGAU C CUGAGACC 2725 GGUCUCAG CUGAUGAGGCCGUUAGGCCGAA AUCAUAAU 9375
1453 GUGAUGAU U CUCUUGAG 2726 CUCAAGAG CUGAUGAGGCCGUUAGGCCGAA AUCAUCAC 9376
1454 UGAUGAUU C UCUUGAGA 2727 UCUCAAGA CUGAUGAGGCCGUUAGGCCGAA AAUCAUCA 9377
1456 AUGAUUCU C UUGAGAGC 2728 GCUCUCAA CUGAUGAGGCCGUUAGGCCGAA AGAAUCAU 9378
1458 GAUUCUCU U GAGAGCAG 2729 CUGCUCUC CUGAUGAGGCCGUUAGGCCGAA AGAGAAUC 9379
1471 GCAGUGAU U AUGAUCCU 2730 AGGAUCAU CUGAUGAGGCCGUUAGGCCGAA AUCACUGC 9380
1472 CAGUGAUU A UGAUCCUG 2731 CAGGAUCA CUGAUGAGGCCGUUAGGCCGAA AAUCACUG 9381
1477 AUUAUGAU C CUGAGAAC 2732 GUUCUCAG CUGAUGAGGCCGUUAGGCCGAA AUCAUAAU 9382
1495 GCAAAAAU A GUUCAAGG 2733 CCUUGAAC CUGAUGAGGCCGUUAGGCCGAA AUUUUUGC 9383
1498 AAAAUAGU U CAAGGUCA 2734 UGACCUUG CUGAUGAGGCCGUUAGGCCGAA ACUAUUUU 9384
1499 AAAUAGUU C AAGGUCAA 2735 UUGACCUU CUGAUGAGGCCGUUAGGCCGAA AACUAUUU 9385
1505 UUCAAGGU C AAAGACUA 2736 UAGUCUUU CUGAUGAGGCCGUUAGGCCGAA ACCUUGAA 9386
1513 CAAAGACU A AGUGCCUU 2737 AAGGCACU CUGAUGAGGCCGUUAGGCCGAA AGUCUUUG 9387
1521 AAGUGCCU U UUCAUCCA 2738 UGGAUGAA CUGAUGAGGCCGUUAGGCCGAA AGGCACUU 9388
1522 AGUGCCUU U UCAUCCAA 2739 UUGGAUGA CUGAUGAGGCCGUUAGGCCGAA AAGGCACU 9389
1523 GUGCCUUU U CAUCCAAA 2740 UUUGGAUG CUGAUGAGGCCGUUAGGCCGAA AAAGGCAC 9390
1524 UGCCUUUU C AUCCAAAU 2741 AUUUGGAU CUGAUGAGGCCGUUAGGCCGAA AAAAGGCA 9391
1527 CUUUUCAU C CAAAUGGA 2742 UCCAUUUG CUGAUGAGGCCGUUAGGCCGAA AUGAAAAG 9392
1538 AAUGGAAU U CUGUGAUA 2743 UAUCACAG CUGAUGAGGCCGUUAGGCCGAA AUUCCAUU 9393
1539 AUGGAAUU C UGUGAUAA 2744 UUAUCACA CUGAUGAGGCCGUUAGGCCGAA AAUUCCAU 9394
1546 UCUGUGAU A AAGGGACC 2745 GGUCCCUU CUGAUGAGGCCGUUAGGCCGAA AUCACAGA 9395
1556 AGGGACCU U GGAACAAU 2746 AUUGUUCC CUGAUGAGGCCGUUAGGCCGAA AGGUCCCU 9396
1569 CAAUGGAU U GAAAAAAG 2747 CUUUUUUC CUGAUGAGGCCGUUAGGCCGAA AUCCAUUG 9397
1593 GAGAAACU A GACAAAGU 2748 ACUUUGUC CUGAUGAGGCCGUUAGGCCGAA AGUUUCUC 9398
1602 GACAAAGU U UUGGCUUU 2749 AAAGCCAA CUGAUGAGGCCGUUAGGCCGAA ACUUUGUC 9399
1603 ACAAAGUU U UGGCUUUG 2750 CAAAGCCA CUGAUGAGGCCGUUAGGCCGAA AACUUUGU 9400
1604 CAAAGUUU U GGCUUUGG 2751 CCAAAGCC CUGAUGAGGCCGUUAGGCCGAA AAACUUUG 9401
1609 UUUUGGCU U UGGAACUC 2752 GAGUUCCA CUGAUGAGGCCGUUAGGCCGAA AGCCAAAA 9402
1610 UUUGGCUU U GGAACUCU 2753 AGAGUUCC CUGAUGAGGCCGUUAGGCCGAA AAGCCAAA 9403
1617 UUGGAACU C UUUGAACA 2754 UGUUCAAA CUGAUGAGGCCGUUAGGCCGAA AGUUCCAA 9404
1619 GGAACUCU U UGAACAAA 2755 UUUGUUCA CUGAUGAGGCCGUUAGGCCGAA AGAGUUCC 9405
1620 GAACUCUU U GAACAAAU 2756 AUUUGUUC CUGAUGAGGCCGUUAGGCCGAA AAGAGUUC 9406
1629 GAACAAAU A ACAAAAGG 2757 CCUUUUGU CUGAUGAGGCCGUUAGGCCGAA AUUUGUUC 9407
1645 GGGUGGAU U AUAUACAU 2758 AUGUAUAU CUGAUGAGGCCGUUAGGCCGAA AUCCACCC 9408
1646 GGUGGAUU A UAUACAUU 2759 AAUGUAUA CUGAUGAGGCCGUUAGGCCGAA AAUCCACC 9409
1648 UGGAUUAU A UACAUUCA 2760 UGAAUGUA CUGAUGAGGCCGUUAGGCCGAA AUAAUCCA 9410
1650 GAUUAUAU A CAUUCAAA 2761 UUUGAAUG CUGAUGAGGCCGUUAGGCCGAA AUAUAAUC 9411
1654 AUAUACAU U CAAAAAAA 2762 UUUUUUUG CUGAUGAGGCCGUUAGGCCGAA AUGUAUAU 9412
1655 UAUACAUU C AAAAAAAU 2763 AUUUUUUU CUGAUGAGGCCGUUAGGCCGAA AAUGUAUA 9413
1664 AAAAAAAU U AAUUCAUA 2764 UAUGAAUU CUGAUGAGGCCGUUAGGCCGAA AUUUUUUU 9414
1665 AAAAAAUU A AUUCAUAG 2765 CUAUGAAU CUGAUGAGGCCGUUAGGCCGAA AAUUUUUU 9415
1668 AAAUUAAU U CAUAGAGA 2766 UCUCUAUG CUGAUGAGGCCGUUAGGCCGAA AUUAAUUU 9416
1669 AAUUAAUU C AUAGAGAU 2767 AUCUCUAU CUGAUGAGGCCGUUAGGCCGAA AAUUAAUU 9417
1672 UAAUUCAU A GAGAUCUU 2768 AAGAUCUC CUGAUGAGGCCGUUAGGCCGAA AUGAAUUA 9418
1678 AUAGAGAU C UUAAGCCA 2769 UGGCUUAA CUGAUGAGGCCGUUAGGCCGAA AUCUCUAU 9419
1680 AGAGAUCU U AAGCCAAG 2770 CUUGGCUU CUGAUGAGGCCGUUAGGCCGAA AGAUCUCU 9420
1681 GAGAUCUU A AGCCAAGU 2771 ACUUGGCU CUGAUGAGGCCGUUAGGCCGAA AAGAUCUC 9421
1690 AGCCAAGU A AUAUAUUC 2772 GAAUAUAU CUGAUGAGGCCGUUAGGCCGAA ACUUGGCU 9422 1693 CAAGUAAU A UAUUCUUA 2773 UAAGAAUA CUGAUGAGGCCGUUAGGCCGAA AUUACUUG 9423
1695 AGUAAUAU A UUCUUAGU 2774 ACUAAGAA CUGAUGAGGCCGUUAGGCCGAA AUAUUACU 9424
1697 UAAUAUAU U CUUAGUAG 2775 CUACUAAG CUGAUGAGGCCGUUAGGCCGAA AUAUAUUA 9425
1698 AAUAUAUU C UUAGUAGA 2776 UCUACUAA CUGAUGAGGCCGUUAGGCCGAA AAUAUAUU 9426
1700 UAUAUUCU U AGUAGAUA 2777 UAUCUACU CUGAUGAGGCCGUUAGGCCGAA AGAAUAUA 9427
1701 AUAUUCUU A GUAGAUAC 2778 GUAUCUAC CUGAUGAGGCCGUUAGGCCGAA AAGAAUAU 9428
1704 UUCUUAGU A GAUACAAA 2779 UUUGUAUC CUGAUGAGGCCGUUAGGCCGAA ACUAAGAA 9429
1708 UAGUAGAU A CAAAACAA 2780 UUGUUUUG CUGAUGAGGCCGUUAGGCCGAA AUCUACUA 9430
1719 AAACAAGU A AAGAUUGG 2781 CCAAUCUU CUGAUGAGGCCGUUAGGCCGAA ACUUGUUU 9431
1725 GUAAAGAU U GGAGACUU 2782 AAGUCUCC CUGAUGAGGCCGUUAGGCCGAA AUCUUUAC 9432
1733 UGGAGACU U UGGACUUG 2783 CAAGUCCA CUGAUGAGGCCGUUAGGCCGAA AGUCUCCA 9433
1734 GGAGACUU U GGACUUGU 2784 ACAAGUCC CUGAUGAGGCCGUUAGGCCGAA AAGUCUCC 9434
1740 UUUGGACU U GUAACAUC 2785 GAUGUUAC CUGAUGAGGCCGUUAGGCCGAA AGUCCAAA 9435
1743 GGACUUGU A ACAUCUCU 2786 AGAGAUGU CUGAUGAGGCCGUUAGGCCGAA ACAAGUCC 9436
1748 UGUAACAU C UCUGAAAA 2787 UUUUCAGA CUGAUGAGGCCGUUAGGCCGAA AUGUUACA 9437
1750 UAACAUCU C UGAAAAAU 2788 AUUUUUCA CUGAUGAGGCCGUUAGGCCGAA AGAUGUUA 9438
1780 CAAGGAGU A AGGGAACU 2789 AGUUCCCU CUGAUGAGGCCGUUAGGCCGAA ACUCCUUG 9439
1789 AGGGAACU U UGCGAUAC 2790 GUAUCGCA CUGAUGAGGCCGUUAGGCCGAA AGUUCCCU 9440
1790 GGGAACUU U GCGAUACA 2791 UGUAUCGC CUGAUGAGGCCGUUAGGCCGAA AAGUUCCC 9441
1796 UUUGCGAU A CAUGAGCC 2792 GGCUCAUG CUGAUGAGGCCGUUAGGCCGAA AUCGCAAA 9442
1815 GAACAGAU U UCUUCGCA 2793 UGCGAAGA CUGAUGAGGCCGUUAGGCCGAA AUCUGUUC 9443
1816 AACAGAUU U CUUCGCAA 2794 UUGCGAAG CUGAUGAGGCCGUUAGGCCGAA AAUCUGUU 9444
1817 ACAGAUUU C UUCGCAAG 2795 CUUGCGAA CUGAUGAGGCCGUUAGGCCGAA AAAUCUGU 9445
1819 AGAUUUCU U CGCAAGAC 2796 GUCUUGCG CUGAUGAGGCCGUUAGGCCGAA AGAAAUCU 9446
1820 GAUUUCUU C GCAAGACU 2797 AGUCUUGC CUGAUGAGGCCGUUAGGCCGAA AAGAAAUC 9447
1829 GCAAGACU A UGGAAAGG 2798 CCUUUCCA CUGAUGAGGCCGUUAGGCCGAA AGUCUUGC 9448
1848 GUGGACCU C UACGCUUU 2799 AAAGCGUA CUGAUGAGGCCGUUAGGCCGAA AGGUCCAC 9449
1850 GGACCUCU A CGCUUUGG 2800 CCAAAGCG CUGAUGAGGCCGUUAGGCCGAA AGAGGUCC 9450
1855 UCUACGCU U UGGGGCUA 2801 UAGCCCCA CUGAUGAGGCCGUUAGGCCGAA AGCGUAGA 9451
1856 CUACGCUU U GGGGCUAA 2802 UUAGCCCC CUGAUGAGGCCGUUAGGCCGAA AAGCGUAG 9452
1863 UUGGGGCU A AUUCUUGC 2803 GCAAGAAU CUGAUGAGGCCGUUAGGCCGAA AGCCCCAA 9453
1866 GGGCUAAU U CUUGCUGA 2804 UCAGCAAG CUGAUGAGGCCGUUAGGCCGAA AUUAGCCC 9454
1867 GGCUAAUU C UUGCUGAA 2805 UUCAGCAA CUGAUGAGGCCGUUAGGCCGAA AAUUAGCC 9455
1869 CUAAUUCU U GCUGAACU 2806 AGUUCAGC CUGAUGAGGCCGUUAGGCCGAA AGAAUUAG 9456
1878 GCUGAACU U CUUCAUGU 2807 ACAUGAAG CUGAUGAGGCCGUUAGGCCGAA AGUUCAGC 9457
1879 CUGAACUU C UUCAUGUA 2808 UACAUGAA CUGAUGAGGCCGUUAGGCCGAA AAGUUCAG 9458
1881 GAACUUCU U CAUGUAUG 2809 CAUACAUG CUGAUGAGGCCGUUAGGCCGAA AGAAGUUC 9459
1882 AACUUCUU C AUGUAUGU 2810 ACAUACAU CUGAUGAGGCCGUUAGGCCGAA AAGAAGUU 9460
1887 CUUCAUGU A UGUGACAC 2811 GUGUCACA CUGAUGAGGCCGUUAGGCCGAA ACAUGAAG 9461
1900 ACACUGCU U UUGAAACA 2812 UGUUUCAA CUGAUGAGGCCGUUAGGCCGAA AGCAGUGU 9462
1901 CACUGCUU U UGAAACAU 2813 AUGUUUCA CUGAUGAGGCCGUUAGGCCGAA AAGCAGUG 9463
1902 ACUGCUUU U GAAACAUC 2814 GAUGUUUC CUGAUGAGGCCGUUAGGCCGAA AAAGCAGU 9464
1910 UGAAACAU C AAAGUUUU 2815 AAAACUUU CUGAUGAGGCCGUUAGGCCGAA AUGUUUCA 9465
1916 AUCAAAGU U UUUCACAG 2816 CUGUGAAA CUGAUGAGGCCGUUAGGCCGAA ACUUUGAU 9466
1917 UCAAAGUU U UUCACAGA 2817 UCUGUGAA CUGAUGAGGCCGUUAGGCCGAA AACUUUGA 9467
1918 CAAAGUUU U UCACAGAC 2818 GUCUGUGA CUGAUGAGGCCGUUAGGCCGAA AAACUUUG 9468
1919 AAAGUUUU U CACAGACC 2819 GGUCUGUG CUGAUGAGGCCGUUAGGCCGAA AAAACUUU 9469
1920 AAGUUUUU C ACAGACCU 2820 AGGUCUGU CUGAUGAGGCCGUUAGGCCGAA AAAAACUU 9470
1929 ACAGACCU A CGGGAUGG 2821 CCAUCCCG CUGAUGAGGCCGUUAGGCCGAA AGGUCUGU 9471
1941 GAUGGCAU C AUCUCAGA 2822 UCUGAGAU CUGAUGAGGCCGUUAGGCCGAA AUGCCAUC 9472
1944 GGCAUCAU C UCAGAUAU 2823 AUAUCUGA CUGAUGAGGCCGUUAGGCCGAA AUGAUGCC 9473 1946 CAUCAUCU C AGAUAUAU 2824 AUAUAUCU CUGAUGAGGCCGUUAGGCCGAA AGAUGAUG 9474
1951 UCUCAGAU A UAUUUGAU 2825 AUCAAAUA CUGAUGAGGCCGUUAGGCCGAA AUCUGAGA 9475
1953 UCAGAUAU A UUUGAUAA 2826 UUAUCAAA CUGAUGAGGCCGUUAGGCCGAA AUAUCUGA 9476
1955 AGAUAUAU U UGAUAAAA 2827 UUUUAUCA CUGAUGAGGCCGUUAGGCCGAA AUAUAUCU 9477
1956 GAUAUAUU U GAUAAAAA 2828 UUUUUAUC CUGAUGAGGCCGUUAGGCCGAA AAUAUAUC 9478
1960 UAUUUGAU A AAAAAGAA 2829 UUCUUUUU CUGAUGAGGCCGUUAGGCCGAA AUCAAAUA 9479
1975 AAAAAACU C UUCUACAG 2830 CUGUAGAA CUGAUGAGGCCGUUAGGCCGAA AGUUUUUU 9480
1977 AAAACUCU U CUACAGAA 2831 UUCUGUAG CUGAUGAGGCCGUUAGGCCGAA AGAGUUUU 9481
1978 AAACUCUU C UACAGAAA 2832 UUUCUGUA CUGAUGAGGCCGUUAGGCCGAA AAGAGUUU 9482
1980 ACUCUUCU A CAGAAAUU 2833 AAUUUCUG CUGAUGAGGCCGUUAGGCCGAA AGAAGAGU 9483
1988 ACAGAAAU U ACUCUCAA 2834 UUGAGAGU CUGAUGAGGCCGUUAGGCCGAA AUUUCUGU 9484
1989 CAGAAAUU A CUCUCAAA 2835 UUUGAGAG CUGAUGAGGCCGUUAGGCCGAA AAUUUCUG 9485
1992 AAAUUACU C UCAAAGAA 2836 UUCUUUGA CUGAUGAGGCCGUUAGGCCGAA AGUAAUUU 9486
1994 AUUACUCU C AAAGAAAC 2837 GUUUCUUU CUGAUGAGGCCGUUAGGCCGAA AGAGUAAU 9487
2011 CUGAGGAU C GACCUAAC 2838 GUUAGGUC CUGAUGAGGCCGUUAGGCCGAA AUCCUCAG 9488
2017 AUCGACCU A ACACAUCU 2839 AGAUGUGU CUGAUGAGGCCGUUAGGCCGAA AGGUCGAU 9489
2024 UAACACAU C UGAAAUAC 2840 GUAUUUCA CUGAUGAGGCCGUUAGGCCGAA AUGUGUUA 9490
2031 UCUGAAAU A CUAAGGAC 2841 GUCCUUAG CUGAUGAGGCCGUUAGGCCGAA AUUUCAGA 9491
2034 GAAAUACU A AGGACCUU 2842 AAGGUCCU CUGAUGAGGCCGUUAGGCCGAA AGUAUUUC 9492
2042 AAGGACCU U GACUGUGU 2843 ACACAGUC CUGAUGAGGCCGUUAGGCCGAA AGGUCCUU 9493
2089 ACACAUGU U AGAGCCCU 2844 AGGGCUCU CUGAUGAGGCCGUUAGGCCGAA ACAUGUGU 9494
2090 CACAUGUU A GAGCCCUU 2845 AAGGGCUC CUGAUGAGGCCGUUAGGCCGAA AACAUGUG 9495
2098 AGAGCCCU U CUGAAAAA 2846 UUUUUCAG CUGAUGAGGCCGUUAGGCCGAA AGGGCUCU 9496
2099 GAGCCCUU C UGAAAAAG 2847 CUUUUUCA CUGAUGAGGCCGUUAGGCCGAA AAGGGCUC 9497
2109 GAAAAAGU A UCCUGCUU 2848 AAGCAGGA CUGAUGAGGCCGUUAGGCCGAA ACUUUUUC 9498
2111 AAAAGUAU C CUGCUUCU 2849 AGAAGCAG CUGAUGAGGCCGUUAGGCCGAA AUACUUUU 9499
2117 AUCCUGCU U CUGAUAUG 2850 CAUAUCAG CUGAUGAGGCCGUUAGGCCGAA AGCAGGAU 9500
2118 UCCUGCUU C UGAUAUGC 2851 GCAUAUCA CUGAUGAGGCCGUUAGGCCGAA AAGCAGGA 9501
2123 CUUCUGAU A UGCAGUUU 2852 AAACUGCA CUGAUGAGGCCGUUAGGCCGAA AUCAGAAG 9502
2130 UAUGCAGU U UUCCUUAA 2853 UUAAGGAA CUGAUGAGGCCGUUAGGCCGAA ACUGCAUA 9503
2131 AUGCAGUU U UCCUUAAA 2854 UUUAAGGA CUGAUGAGGCCGUUAGGCCGAA AACUGCAU 9504
2132 UGCAGUUU U CCUUAAAU 2855 AUUUAAGG CUGAUGAGGCCGUUAGGCCGAA AAACUGCA 9505
2133 GCAGUUUU C CUUAAAUU 2856 AAUUUAAG CUGAUGAGGCCGUUAGGCCGAA AAAACUGC 9506
2136 GUUUUCCU U AAAUUAUC 2857 GAUAAUUU CUGAUGAGGCCGUUAGGCCGAA AGGAAAAC 9507
2137 UUUUCCUU A AAUUAUCU 2858 AGAUAAUU CUGAUGAGGCCGUUAGGCCGAA AAGGAAAA 9508
2141 CCUUAAAU U AUCUAAAA 2859 UUUUAGAU CUGAUGAGGCCGUUAGGCCGAA AUUUAAGG 9509
2142 CUUAAAUU A UCUAAAAU 2860 AUUUUAGA CUGAUGAGGCCGUUAGGCCGAA AAUUUAAG 9510
2144 UAAAUUAU C UAAAAUCU 2861 AGAUUUUA CUGAUGAGGCCGUUAGGCCGAA AUAAUUUA 9511
2146 AAUUAUCU A AAAUCUGC 2862 GCAGAUUU CUGAUGAGGCCGUUAGGCCGAA AGAUAAUU 9512
2151 UCUAAAAU C UGCUAGGG 2863 CCCUAGCA CUGAUGAGGCCGUUAGGCCGAA AUUUUAGA 9513
2156 AAUCUGCU A GGGAAUAU 2864 AUAUUCCC CUGAUGAGGCCGUUAGGCCGAA AGCAGAUU 9514
2163 UAGGGAAU A UCAAUAGA 2865 UCUAUUGA CUGAUGAGGCCGUUAGGCCGAA AUUCCCUA 9515
2165 GGGAAUAU C AAUAGAUA 2866 UAUCUAUU CUGAUGAGGCCGUUAGGCCGAA AUAUUCCC 9516
2169 AUAUCAAU A GAUAUUUA 2867 UAAAUAUC CUGAUGAGGCCGUUAGGCCGAA AUUGAUAU 9517
2173 CAAUAGAU A UUUACCUU 2868 AAGGUAAA CUGAUGAGGCCGUUAGGCCGAA AUCUAUUG 9518
2175 AUAGAUAU U UACCUUUU 2869 AAAAGGUA CUGAUGAGGCCGUUAGGCCGAA AUAUCUAU 9519
2176 UAGAUAUU U ACCUUUUA 2870 UAAAAGGU CUGAUGAGGCCGUUAGGCCGAA AAUAUCUA 9520
2177 AGAUAUUU A CCUUUUAU 2871 AUAAAAGG CUGAUGAGGCCGUUAGGCCGAA AAAUAUCU 9521
2181 AUUUACCU U UUAUUUUA 2872 UAAAAUAA CUGAUGAGGCCGUUAGGCCGAA AGGUAAAU 9522
2182 UUUACCUU U UAUUUUAA 2873 UUAAAAUA CUGAUGAGGCCGUUAGGCCGAA AAGGUAAA 9523
2183 UUACCUUU U AUUUUAAU 2874 AUUAAAAU CUGAUGAGGCCGUUAGGCCGAA AAAGGUAA 9524 2184 UACCUUUU A UUUUAAUG 2875 CAUUAAAA CUGAUGAGGCCGUUAGGCCGAA AAAAGGUA 9525
2186 CCUUUUAU U UUAAUGUU 2876 AACAUUAA CUGAUGAGGCCGUUAGGCCGAA AUAAAAGG 9526
2187 CUUUUAUU U UAAUGUUU 2877 AAACAUUA CUGAUGAGGCCGUUAGGCCGAA AAUAAAAG 9527
2188 UUUUAUUU U AAUGUUUC 2878 GAAACAUU CUGAUGAGGCCGUUAGGCCGAA AAAUAAAA 9528
2189 UUUAUUUU A AUGUUUCC 2879 GGAAACAU CUGAUGAGGCCGUUAGGCCGAA AAAAUAAA 9529
2194 UUUAAUGU U UCCUUUAA 2880 UUAAAGGA CUGAUGAGGCCGUUAGGCCGAA ACAUUAAA 9530
2195 UUAAUGUU U CCUUUAAU 2881 AUUAAAGG CUGAUGAGGCCGUUAGGCCGAA AACAUUAA 9531
2196 UAAUGUUU C CUUUAAUU 2882 AAUUAAAG CUGAUGAGGCCGUUAGGCCGAA AAACAUUA 9532
2199 UGUUUCCU U UAAUUUUU 2883 AAAAAUUA CUGAUGAGGCCGUUAGGCCGAA AGGAAACA 9533
2200 GUUUCCUU U AAUUUUUU 2884 AAAAAAUU CUGAUGAGGCCGUUAGGCCGAA AAGGAAAC 9534
2201 UUUCCUUU A AUUUUUUA 2885 UAAAAAAU CUGAUGAGGCCGUUAGGCCGAA AAAGGAAA 9535
2204 CCUUUAAU U UUUUACUA 2886 UAGUAAAA CUGAUGAGGCCGUUAGGCCGAA AUUAAAGG 9536
2205 CUUUAAUU U UUUACUAU 2887 AUAGUAAA CUGAUGAGGCCGUUAGGCCGAA AAUUAAAG 9537
2206 UUUAAUUU U UUACUAUU 2888 AAUAGUAA CUGAUGAGGCCGUUAGGCCGAA AAAUUAAA 9538
2207 UUAAUUUU U UACUAUUU 2889 AAAUAGUA CUGAUGAGGCCGUUAGGCCGAA AAAAUUAA 9539
2208 UAAUUUUU U ACUAUUUU 2890 AAAAUAGU CUGAUGAGGCCGUUAGGCCGAA AAAAAUUA 9540
2209 AAUUUUUU A CUAUUUUU 2891 AAAAAUAG CUGAUGAGGCCGUUAGGCCGAA AAAAAAUU 9541
2212 UUUUUACU A UUUUUACU 2892 AGUAAAAA CUGAUGAGGCCGUUAGGCCGAA AGUAAAAA 9542
2214 UUUACUAU U UUUACUAA 2893 UUAGUAAA CUGAUGAGGCCGUUAGGCCGAA AUAGUAAA 9543
2215 UUACUAUU U UUACUAAU 2894 AUUAGUAA CUGAUGAGGCCGUUAGGCCGAA AAUAGUAA 9544
2216 UACUAUUU U UACUAAUC 2895 GAUUAGUA CUGAUGAGGCCGUUAGGCCGAA AAAUAGUA 9545
2217 ACUAUUUU U ACUAAUCU 2896 AGAUUAGU CUGAUGAGGCCGUUAGGCCGAA AAAAUAGU 9546
2218 CUAUUUUU A CUAAUCUU 2897 AAGAUUAG CUGAUGAGGCCGUUAGGCCGAA AAAAAUAG 9547
2221 UUUUUACU A AUCUUUCU 2898 AGAAAGAU CUGAUGAGGCCGUUAGGCCGAA AGUAAAAA 9548
2224 UUACUAAU C UUUCUGCA 2899 UGCAGAAA CUGAUGAGGCCGUUAGGCCGAA AUUAGUAA 9549
2226 ACUAAUCU U UCUGCAGA 2900 UCUGCAGA CUGAUGAGGCCGUUAGGCCGAA AGAUUAGU 9550
2227 CUAAUCUU U CUGCAGAA 2901 UUCUGCAG CUGAUGAGGCCGUUAGGCCGAA AAGAUUAG 9551
2228 UAAUCUUU C UGCAGAAA 2902 UUUCUGCA CUGAUGAGGCCGUUAGGCCGAA AAAGAUUA 9552
2246 AGAAAGGU U UUCUUCUU 2903 AAGAAGAA CUGAUGAGGCCGUUAGGCCGAA ACCUUUCU 9553
2247 GAAAGGUU U UCUUCUUU 2904 AAAGAAGA CUGAUGAGGCCGUUAGGCCGAA AACCUUUC 9554
2248 AAAGGUUU U CUUCUUUU 2905 AAAAGAAG CUGAUGAGGCCGUUAGGCCGAA AAACCUUU 9555
2249 AAGGUUUU C UUCUUUUU 2906 AAAAAGAA CUGAUGAGGCCGUUAGGCCGAA AAAACCUU 9556
2251 GGUUUUCU U CUUUUUGC 2907 GCAAAAAG CUGAUGAGGCCGUUAGGCCGAA AGAAAACC 9557
2252 GUUUUCUU C UUUUUGCU 2908 AGCAAAAA CUGAUGAGGCCGUUAGGCCGAA AAGAAAAC 9558
2254 UUUCUUCU U UUUGCUUC 2909 GAAGCAAA CUGAUGAGGCCGUUAGGCCGAA AGAAGAAA 9559
2255 UUCUUCUU U UUGCUUCA 2910 UGAAGCAA CUGAUGAGGCCGUUAGGCCGAA AAGAAGAA 9560
2256 ucuucuuu U UGCUUCAA 2911 UUGAAGCA CUGAUGAGGCCGUUAGGCCGAA AAAGAAGA 9561
2257 cuucuuuu U GCUUCAAA 2912 UUUGAAGC CUGAUGAGGCCGUUAGGCCGAA AAAAGAAG 9562
2261 UUUUUGCU U CAAAAACA 2913 UGUUUUUG CUGAUGAGGCCGUUAGGCCGAA AGCAAAAA 9563
2262 UUUUGCUU c AAAAACAU 2914 AUGUUUUU CUGAUGAGGCCGUUAGGCCGAA AAGCAAAA 9564
2271 AAAAACAU u CUUACAUU 2915 AAUGUAAG CUGAUGAGGCCGUUAGGCCGAA AUGUUUUU 9565
2272 AAAACAUU c UUACAUUU 2916 AAAUGUAA CUGAUGAGGCCGUUAGGCCGAA AAUGUUUU 9566
2274 AACAUUCU u ACAUUUUA 2917 UAAAAUGU CUGAUGAGGCCGUUAGGCCGAA AGAAUGUU 9567
2275 ACAUUCUU A CAUUUUAC 2918 GUAAAAUG CUGAUGAGGCCGUUAGGCCGAA AAGAAUGU 9568
2279 UCUUACAU U UUACUUUU 2919 AAAAGUAA CUGAUGAGGCCGUUAGGCCGAA AUGUAAGA 9569
2280 CUUACAUU U UACUUUUU 2920 AAAAAGUA CUGAUGAGGCCGUUAGGCCGAA AAUGUAAG 9570
2281 UUACAUUU U ACUUUUUC 2921 GAAAAAGU CUGAUGAGGCCGUUAGGCCGAA AAAUGUAA 9571
2282 UACAUUUU A cuuuuucc 2922 GGAAAAAG CUGAUGAGGCCGUUAGGCCGAA AAAAUGUA 9572
2285 AUUUUACU U UUUCCUGG 2923 CCAGGAAA CUGAUGAGGCCGUUAGGCCGAA AGUAAAAU 9573
2286 UUUUACUU U UUCCUGGC 2924 GCCAGGAA CUGAUGAGGCCGUUAGGCCGAA AAGUAAAA 9574
2287 UUUACUUU U UCCUGGCU 2925 AGCCAGGA CUGAUGAGGCCGUUAGGCCGAA AAAGUAAA 9575 2288 UUACUUUU U CCUGGCUC 2926 GAGCCAGG CUGAUGAGGCCGUUAGGCCGAA AAAAGUAA 9576
2289 UACUUUUU C CUGGCUCA 2927 UGAGCCAG CUGAUGAGGCCGUUAGGCCGAA AAAAAGUA 9577
2296 UCCUGGCU C AUCUCUUU 2928 AAAGAGAU CUGAUGAGGCCGUUAGGCCGAA AGCCAGGA 9578
2299 UGGCUCAU C UCUUUAUU 2929 AAUAAAGA CUGAUGAGGCCGUUAGGCCGAA AUGAGCCA 9579
2301 GCUCAUCU C UUUAUUCU 2930 AGAAUAAA CUGAUGAGGCCGUUAGGCCGAA AGAUGAGC 9580
2303 UCAUCUCU U UAUUCUUU 2931 AAAGAAUA CUGAUGAGGCCGUUAGGCCGAA AGAGAUGA 9581
2304 CAUCUCUU U AUUCUUUU 2932 AAAAGAAU CUGAUGAGGCCGUUAGGCCGAA AAGAGAUG 9582
2305 AUCUCUUU A UUCUUUUU 2933 AAAAAGAA CUGAUGAGGCCGUUAGGCCGAA AAAGAGAU 9583
2307 CUCUUUAU U CUUUUUUU 2934 AAAAAAAG CUGAUGAGGCCGUUAGGCCGAA AUAAAGAG 9584
2308 UCUUUAUU C uuuuuuuu 2935 AAAAAAAA CUGAUGAGGCCGUUAGGCCGAA AAUAAAGA 9585
2310 UUUAUUCU U uuuuuuuu 2936 AAAAAAAA CUGAUGAGGCCGUUAGGCCGAA AGAAUAAA 9586
2311 UUAUUCUU U uuuuuuuu 2937 AAAAAAAA CUGAUGAGGCCGUUAGGCCGAA AAGAAUAA 9587
2312 UAUUCUUU U uuuuuuuu 2938 AAAAAAAA CUGAUGAGGCCGUUAGGCCGAA AAAGAAUA 9588
2313 AUUCUUUU U uuuuuuuu 2939 AAAAAAAA CUGAUGAGGCCGUUAGGCCGAA AAAAGAAU 9589
2314 UUCUUUUU U uuuuuuuu 2940 AAAAAAAA CUGAUGAGGCCGUUAGGCCGAA AAAAAGAA 9590
2315 ucuuuuuu U UUUUUUUA 2941 UAAAAAAA CUGAUGAGGCCGUUAGGCCGAA AAAAAAGA 9591
2316 cuuuuuuu U UUUUUUAA 2942 UUAAAAAA CUGAUGAGGCCGUUAGGCCGAA AAAAAAAG 9592
2317 uuuuuuuu U UUUUUAAA 2943 UUUAAAAA CUGAUGAGGCCGUUAGGCCGAA AAAAAAAA 9593
2318 uuuuuuuu U UUUUAAAG 2944 CUUUAAAA CUGAUGAGGCCGUUAGGCCGAA AAAAAAAA 9594
2319 uuuuuuuu U UUUAAAGA 2945 UCUUUAAA CUGAUGAGGCCGUUAGGCCGAA AAAAAAAA 9595
2320 uuuuuuuu u UUAAAGAC 2946 GUCUUUAA CUGAUGAGGCCGUUAGGCCGAA AAAAAAAA 9596
2321 uuuuuuuu u UAAAGACA 2947 UGUCUUUA CUGAUGAGGCCGUUAGGCCGAA AAAAAAAA 9597
2322 uuuuuuuu u AAAGACAG 2948 CUGUCUUU CUGAUGAGGCCGUUAGGCCGAA AAAAAAAA 9598
2323 uuuuuuuu A AAGACAGA 2949 UCUGUCUU CUGAUGAGGCCGUUAGGCCGAA AAAAAAAA 9599
2334 GACAGAGU C UCGCUCUG 2950 CAGAGCGA CUGAUGAGGCCGUUAGGCCGAA ACUCUGUC 9600
2336 CAGAGUCU C GCUCUGUU 2951 AACAGAGC CUGAUGAGGCCGUUAGGCCGAA AGACUCUG 9601
2340 GUCUCGCU C UGUUGCCC 2952 GGGCAACA CUGAUGAGGCCGUUAGGCCGAA AGCGAGAC 9602
2344 CGCUCUGU u GCCCAGGC 2953 GCCUGGGC CUGAUGAGGCCGUUAGGCCGAA ACAGAGCG 9603
2372 GACACAGU c UUGGCUCA 2954 UGAGCCAA CUGAUGAGGCCGUUAGGCCGAA ACUGUGUC 9604
2374 CACAGUCU u GGCUCACU 2955 AGUGAGCC CUGAUGAGGCCGUUAGGCCGAA AGACUGUG 9605
2379 UCUUGGCU c ACUGCAAC 2956 GUUGCAGU CUGAUGAGGCCGUUAGGCCGAA AGCCAAGA 9606
2389 CUGCAACU u CUGCCUCU 2957 AGAGGCAG CUGAUGAGGCCGUUAGGCCGAA AGUUGCAG 9607
2390 UGCAACUU c UGCCUCUU 2958 AAGAGGCA CUGAUGAGGCCGUUAGGCCGAA AAGUUGCA 9608
2396 UUCUGCCU c UUGGGUUC 2959 GAACCCAA CUGAUGAGGCCGUUAGGCCGAA AGGCAGAA 9609
2398 CUGCCUCU u GGGUUCAA 2960. UUGAACCC CUGAUGAGGCCGUUAGGCCGAA AGAGGCAG 9610
2403 UCUUGGGU u CAAGUGAU 2961 AUCACUUG CUGAUGAGGCCGUUAGGCCGAA ACCCAAGA 9611
2404 CUUGGGUU c AAGUGAUU 2962 AAUCACUU CUGAUGAGGCCGUUAGGCCGAA AACCCAAG 9612
2412 CAAGUGAU u CUCCUGCC 2963 GGCAGGAG CUGAUGAGGCCGUUAGGCCGAA AUCACUUG 9613
2413 AAGUGAUU c UCCUGCCU 2964 AGGCAGGA CUGAUGAGGCCGUUAGGCCGAA AAUCACUU 9614
2415 GUGAUUCU c CUGCCUCA 2965 UGAGGCAG CUGAUGAGGCCGUUAGGCCGAA AGAAUCAC 9615
2422 UCCUGCCU c AGCCUCCU 2966 AGGAGGCU CUGAUGAGGCCGUUAGGCCGAA AGGCAGGA 9616
2428 CUCAGCCU c CUGAGUAG 2967 CUACUCAG CUGAUGAGGCCGUUAGGCCGAA AGGCUGAG 9617
2435 UCCUGAGU A GCUGGAUU 2968 AAUCCAGC CUGAUGAGGCCGUUAGGCCGAA ACUCAGGA 9618
2443 AGCUGGAU u ACAGGCAU 2969 AUGCCUGU CUGAUGAGGCCGUUAGGCCGAA AUCCAGCU 9619
2444 GCUGGAUU A CAGGCAUG 2970 CAUGCCUG CUGAUGAGGCCGUUAGGCCGAA AAUCCAGC 9620
2469 ACCCAACU A AUUUUUGU 2971 ACAAAAAU CUGAUGAGGCCGUUAGGCCGAA AGUUGGGU 9621
2472 CAACUAAU U UUUGUGUU 2972 AACACAAA CUGAUGAGGCCGUUAGGCCGAA AUUAGUUG 9622
2473 AACUAAUU U UUGUGUUU 2973 AAACACAA CUGAUGAGGCCGUUAGGCCGAA AAUUAGUU 9623
2474 ACUAAUUU U UGUGUUUU 2974 AAAACACA CUGAUGAGGCCGUUAGGCCGAA AAAUUAGU 9624
2475 CUAAUUUU U GUGUUUUU 2975 AAAAACAC CUGAUGAGGCCGUUAGGCCGAA AAAAUUAG 9625
2480 UUUUGUGU U UUUAAUAA 2976 UUAUUAAA CUGAUGAGGCCGUUAGGCCGAA ACACAAAA 9626 2481 UUUGUGUU U UUAAUAAA 2977 UUUAUUAA CUGAUGAGGCCGUUAGGCCGAA AACACAAA 9627
2482 UUGUGUUU U UAAUAAAG 2978 CUUUAUUA CUGAUGAGGCCGUUAGGCCGAA AAACACAA 9628
2483 UGUGUUUU U AAUAAAGA 2979 UCUUUAUU CUGAUGAGGCCGUUAGGCCGAA AAAACACA 9629
2484 GUGUUUUU A AUAAAGAC 2980 GUCUUUAU CUGAUGAGGCCGUUAGGCCGAA AAAAACAC 9630
2487 UUUUUAAU A AAGACAGG 2981 CCUGUCUU CUGAUGAGGCCGUUAGGCCGAA AUUAAAAA 9631
2498 GACAGGGU U UCACCAUG 2982 CAUGGUGA CUGAUGAGGCCGUUAGGCCGAA ACCCUGUC 9632
2499 ACAGGGUU U CACCAUGU 2983 ACAUGGUG CUGAUGAGGCCGUUAGGCCGAA AACCCUGU 9633
2500 CAGGGUUU C ACCAUGUU 2984 AACAUGGU CUGAUGAGGCCGUUAGGCCGAA AAACCCUG 9634
2508 CACCAUGU U GGCCAGGC 2985 GCCUGGCC CUGAUGAGGCCGUUAGGCCGAA ACAUGGUG 9635
2521 AGGCUGGU C UCAAACUC 2986 GAGUUUGA CUGAUGAGGCCGUUAGGCCGAA ACCAGCCU 9636
2523 GCUGGUCU C AAACUCCU 2987 AGGAGUUU CUGAUGAGGCCGUUAGGCCGAA AGACCAGC 9637
2529 CUCAAACU C CUGACCUC 2988 GAGGUCAG CUGAUGAGGCCGUUAGGCCGAA AGUUUGAG 9638
2537 CCUGACCU C AAGUAAUC 2989 GAUUACUU CUGAUGAGGCCGUUAGGCCGAA AGGUCAGG 9639
2542 CCUCAAGU A AUCCACCU 2990 AGGUGGAU CUGAUGAGGCCGUUAGGCCGAA ACUUGAGG 9640
2545 CAAGUAAU C CACCUGCC 2991 GGCAGGUG CUGAUGAGGCCGUUAGGCCGAA AUUACUUG 9641
2555 ACCUGCCU C GGCCUCCC 2992 GGGAGGCC CUGAUGAGGCCGUUAGGCCGAA AGGCAGGU 9642
2561 CUCGGCCU C CCAAAGUG 2993 CACUUUGG CUGAUGAGGCCGUUAGGCCGAA AGGCCGAG 9643
2577 GCUGGGAU U ACAGGGAU 2994 AUCCCUGU CUGAUGAGGCCGUUAGGCCGAA AUCCCAGC 9644
2578 CUGGGAUU A CAGGGAUG 2995 CAUCCCUG CUGAUGAGGCCGUUAGGCCGAA AAUCCCAG 9645
2605 CCCAGCCU C AUCUCUUU 2996 AAAGAGAU CUGAUGAGGCCGUUAGGCCGAA AGGCUGGG 9646
2608 AGCCUCAU C UCUUUGUU 2997 AACAAAGA CUGAUGAGGCCGUUAGGCCGAA AUGAGGCU 9647
2610 CCUCAUCU C UUUGUUCU 2998 AGAACAAA CUGAUGAGGCCGUUAGGCCGAA AGAUGAGG 9648
2612 UCAUCUCU U UGUUCUAA 2999 UUAGAACA CUGAUGAGGCCGUUAGGCCGAA AGAGAUGA 9649
2613 CAUCUCUU U GUUCUAAA 3000 UUUAGAAC CUGAUGAGGCCGUUAGGCCGAA AAGAGAUG 9650
2616 CUCUUUGU U CUAAAGAU 3001 AUCUUUAG CUGAUGAGGCCGUUAGGCCGAA ACAAAGAG 9651
2617 UCUUUGUU C UAAAGAUG 3002 CAUCUUUA CUGAUGAGGCCGUUAGGCCGAA AACAAAGA 9652
2619 UUUGUUCU A AAGAUGGA 3003 UCCAUCUU CUGAUGAGGCCGUUAGGCCGAA AGAACAAA 9653
2644 CCCCAAAU U UUCUUUUU 3004 AAAAAGAA CUGAUGAGGCCGUUAGGCCGAA AUUUGGGG 9654
2645 CCCAAAUU U UCUUUUUA 3005 UAAAAAGA CUGAUGAGGCCGUUAGGCCGAA AAUUUGGG 9655
2646 CCAAAUUU U CUUUUUAU 3006 AUAAAAAG CUGAUGAGGCCGUUAGGCCGAA AAAUUUGG 9656
2647 CAAAUUUU C UUUUUAUA 3007 UAUAAAAA CUGAUGAGGCCGUUAGGCCGAA AAAAUUUG 9657
2649 AAUUUUCU U UUUAUACU 3008 AGUAUAAA CUGAUGAGGCCGUUAGGCCGAA AGAAAAUU 9658
2650 AUUUUCUU U UUAUACUA 3009 UAGUAUAA CUGAUGAGGCCGUUAGGCCGAA AAGAAAAU 9659
2651 UUUUCUUU U UAUACUAU 3010 AUAGUAUA CUGAUGAGGCCGUUAGGCCGAA AAAGAAAA 9660
2652 UUUCUUUU U AUACUAUU 3011 AAUAGUAU CUGAUGAGGCCGUUAGGCCGAA AAAAGAAA 9661
2653 UUCUUUUU A UACUAUUA 3012 UAAUAGUA CUGAUGAGGCCGUUAGGCCGAA AAAAAGAA 9662
2655 CUUUUUAU A CUAUUAAU 3013 AUUAAUAG CUGAUGAGGCCGUUAGGCCGAA AUAAAAAG 9663
2658 UUUAUACU A UUAAUGAA 3014 UUCAUUAA CUGAUGAGGCCGUUAGGCCGAA AGUAUAAA 9664
2660 UAUACUAU U AAUGAAUC 3015 GAUUCAUU CUGAUGAGGCCGUUAGGCCGAA AUAGUAUA 9665
2661 AUACUAUU A AUGAAUCA 3016 UGAUUCAU CUGAUGAGGCCGUUAGGCCGAA AAUAGUAU 9666
2668 UAAUGAAU C AAUCAAUU 3017 AAUUGAUU CUGAUGAGGCCGUUAGGCCGAA AUUCAUUA 9667
2672 GAAUCAAU C AAUUCAUA 3018 UAUGAAUU CUGAUGAGGCCGUUAGGCCGAA AUUGAUUC 9668
2676 CAAUCAAU U CAUAUCUA 3019 UAGAUAUG CUGAUGAGGCCGUUAGGCCGAA AUUGAUUG 9669
2677 AAUCAAUU C AUAUCUAU 3020 AUAGAUAU CUGAUGAGGCCGUUAGGCCGAA AAUUGAUU 9670
2680 CAAUUCAU A UCUAUUUA 3021 UAAAUAGA CUGAUGAGGCCGUUAGGCCGAA AUGAAUUG 9671
2682 AUUCAUAU C UAUUUAUU 3022 AAUAAAUA CUGAUGAGGCCGUUAGGCCGAA AUAUGAAU 9672
2684 UCAUAUCU A UUUAUUAA 3023 UUAAUAAA CUGAUGAGGCCGUUAGGCCGAA AGAUAUGA 9673
2686 AUAUCUAU U UAUUAAAU 3024 AUUUAAUA CUGAUGAGGCCGUUAGGCCGAA AUAGAUAU 9674
2687 UAUCUAUU U AUUAAAUU 3025 AAUUUAAU CUGAUGAGGCCGUUAGGCCGAA AAUAGAUA 9675
2688 AUCUAUUU A UUAAAUUU 3026 AAAUUUAA CUGAUGAGGCCGUUAGGCCGAA AAAUAGAU 9676
2690 CUAUUUAU U AAAUUUCU 3027 AGAAAUUU CUGAUGAGGCCGUUAGGCCGAA AUAAAUAG 9677 2691 UAUUUAUU A AAUUUCUA 3028 UAGAAAUU CUGAUGAGGCCGUUAGGCCGAA AAUAAAUA 9678
2695 UAUUAAAU U UCUACCGC 3029 GCGGUAGA CUGAUGAGGCCGUUAGGCCGAA AUUUAAUA 9679
2696 AUUAAAUU U CUACCGCU 3030 AGCGGUAG CUGAUGAGGCCGUUAGGCCGAA AAUUUAAU 9680
2697 UUAAAUUU C UACCGCUU 3031 AAGCGGUA CUGAUGAGGCCGUUAGGCCGAA AAAUUUAA 9681
2699 AAAUUUCU A CCGCUUUU 3032 AAAAGCGG CUGAUGAGGCCGUUAGGCCGAA AGAAAUUU 9682
2705 CUACCGCU U UUAGGCCA 3033 UGGCCUAA CUGAUGAGGCCGUUAGGCCGAA AGCGGUAG 9683
2706 UACCGCUU U UAGGCCAA 3034 UUGGCCUA CUGAUGAGGCCGUUAGGCCGAA AAGCGGUA 9684
2707 ACCGCUUU U AGGCCAAA 3035 UUUGGCCU CUGAUGAGGCCGUUAGGCCGAA AAAGCGGU 9685
2708 CCGCUUUU A GGCCAAAA 3036 UUUUGGCC CUGAUGAGGCCGUUAGGCCGAA AAAAGCGG 9686
2723 AAAAAUGU A AGAUCGUU 3037 AACGAUCU CUGAUGAGGCCGUUAGGCCGAA ACAUUUUU 9687
2728 UGUAAGAU C GUUCUCUG 3038 CAGAGAAC CUGAUGAGGCCGUUAGGCCGAA AUCUUACA 9688
2731 AAGAUCGU U CUCUGCCU 3039 AGGCAGAG CUGAUGAGGCCGUUAGGCCGAA ACGAUCUU 9689
2732 AGAUCGUU C UCUGCCUC 3040 GAGGCAGA CUGAUGAGGCCGUUAGGCCGAA AACGAUCU 9690
2734 AUCGUUCU C UGCCUCAC 3041 GUGAGGCA CUGAUGAGGCCGUUAGGCCGAA AGAACGAU 9691
2740 CUCUGCCU C ACAUAGCU 3042 AGCUAUGU CUGAUGAGGCCGUUAGGCCGAA AGGCAGAG 9692
2745 CCUCACAU A GCUUACAA 3043 UUGUAAGC CUGAUGAGGCCGUUAGGCCGAA AUGUGAGG 9693
2749 ACAUAGCU U ACAAGCCA 3044 UGGCUUGU CUGAUGAGGCCGUUAGGCCGAA AGCUAUGU 9694
2750 CAUAGCUU A CAAGCCAG 3045 CUGGCUUG CUGAUGAGGCCGUUAGGCCGAA AAGCUAUG 9695
2769 GGAGAAAU A UGGUACUC 3046 GAGUACCA CUGAUGAGGCCGUUAGGCCGAA AUUUCUCC 9696
2774 AAUAUGGU A CUCAUUAA 3047 UUAAUGAG CUGAUGAGGCCGUUAGGCCGAA ACCAUAUU 9697
2777 AUGGUACU C AUUAAAAA 3048 UUUUUAAU CUGAUGAGGCCGUUAGGCCGAA AGUACCAU 9698
2780 GUACUCAU U AAAAAAAA 3049 UUUUUUUU CUGAUGAGGCCGUUAGGCCGAA AUGAGUAC 9699
2781 UACUCAUU A AAAAAAAA 3050 UUUUUUUU CUGAUGAGGCCGUUAGGCCGAA AAUGAGUA 9700
Input Sequence = NM_002759. Cut Site = UH/ .
Arm Length = 8. Core Sequence = CUGAUGAG GCCGUUAGGC CGAA
NM_002759 (Homo sapiens protein kinase, interferon-inducible double stranded RNA dependent (PRKR) , mRNA.; 2808 bp)
Underlined region can be any X sequence or linker, as described herein.
Table XIV: Human PKR Inozyme and Substrate Sequence
Pos Substrate Seq Inozyme Seq ID ID
17 GGCGGCGC A GUUUGCUC 3051 GAGCAAAC CUGAUGAGGCCGUUAGGCCGAA ICGCCGCC 9701
24 CAGUUUGC U CAUACUUU 3052 AAAGUAUG CUGAUGAGGCCGUUAGGCCGAA ICAAACUG 9702
26 GUUUGCUC A UACUUUGU 3053 ACAAAGUA CUGAUGAGGCCGUUAGGCCGAA IAGCAAAC 9703
30 GCUCAUAC U UUGUGACU 3054 AGUCACAA CUGAUGAGGCCGUUAGGCCGAA IUAUGAGC 9704
38 UUUGUGAC U UGCGGUCA 3055 UGACCGCA CUGAUGAGGCCGUUAGGCCGAA IUCACAAA 9705
46 UUGCGGUC A CAGUGGCA 3056 UGCCACUG CUGAUGAGGCCGUUAGGCCGAA lACCGCAA 9706
48 GCGGUCAC A GUGGCAUU 3057 AAUGCCAC CUGAUGAGGCCGUUAGGCCGAA IUGACCGC 9707
54 ACAGUGGC A UUCAGCUC 3058 GAGCUGAA CUGAUGAGGCCGUUAGGCCGAA ICCACUGU 9708
58 UGGCAUUC A GCUCCACA 3059 UGUGGAGC CUGAUGAGGCCGUUAGGCCGAA lAAUGCCA 9709
61 CAUUCAGC U CCACACUU 3060 AAGUGUGG CUGAUGAGGCCGUUAGGCCGAA ICUGAAUG 9710
63 UUCAGCUC C ACACUUGG 3061 CCAAGUGU CUGAUGAGGCCGUUAGGCCGAA IAGCUGAA 9711
64 UCAGCUCC A CACUUGGU 3062 ACCAAGUG CUGAUGAGGCCGUUAGGCCGAA IGAGCUGA 9712
66 AGCUCCAC A CUUGGUAG 3063 CUACCAAG CUGAUGAGGCCGUUAGGCCGAA IUGGAGCU 9713
68 CUCCACAC U UGGUAGAA 3064 UUCUACCA CUGAUGAGGCCGUUAGGCCGAA IUGUGGAG 9714
78 GGUAGAAC C ACAGGCAC 3065 GUGCCUGU CUGAUGAGGCCGUUAGGCCGAA IUUCUACC 9715
79 GUAGAACC A CAGGCACG 3066 CGUGCCUG CUGAUGAGGCCGUUAGGCCGAA IGUUCUAC 9716
81 AGAACCAC A GGCACGAC 3067 GUCGUGCC CUGAUGAGGCCGUUAGGCCGAA IUGGUUCU 9717
85 CCACAGGC A CGACAAGC 3068 GCUUGUCG CUGAUGAGGCCGUUAGGCCGAA ICCUGUGG 9718
90 GGCACGAC A AGCAUAGA 3069 UCUAUGCU CUGAUGAGGCCGUUAGGCCGAA IUCGUGCC 9719
94 CGACAAGC A UAGAAACA 3070 UGUUUCUA CUGAUGAGGCCGUUAGGCCGAA ICUUGUCG 9720
102 AUAGAAAC A UCCUAAAC 3071 GUUUAGGA CUGAUGAGGCCGUUAGGCCGAA IUUUCUAU 9721
105 GAAACAUC C UAAACAAU 3072 AUUGUUUA CUGAUGAGGCCGUUAGGCCGAA IAUGUUUC 9722
106 AAACAUCC U AAACAAUC 3073 GAUUGUUU CUGAUGAGGCCGUUAGGCCGAA IGAUGUUU 9723
111 UCCUAAAC A AUCUUCAU 3074 AUGAAGAU CUGAUGAGGCCGUUAGGCCGAA lUUUAGGA 9724
115 AAACAAUC U UCAUCGAG 3075 CUCGAUGA CUGAUGAGGCCGUUAGGCCGAA IAUUGUUU 9725
118 CAAUCUUC A UCGAGGCA 3076 UGCCUCGA CUGAUGAGGCCGUUAGGCCGAA IAAGAUUG 9726
126 AUCGAGGC A UCGAGGUC 3077 GACCUCGA CUGAUGAGGCCGUUAGGCCGAA ICCUCGAU 9727
135 UCGAGGUC C AUCCCAAU 3078 AUUGGGAU CUGAUGAGGCCGUUAGGCCGAA IACCUCGA 9728
136 CGAGGUCC A UCCCAAUA 3079 UAUUGGGA CUGAUGAGGCCGUUAGGCCGAA IGACCUCG 9729
139 GGUCCAUC C CAAUAAAA 3080 UUUUAUUG CUGAUGAGGCCGUUAGGCCGAA IAUGGACC 9730
140 GUCCAUCC C AAUAAAAA 3081 UUUUUAUU CUGAUGAGGCCGUUAGGCCGAA IGAUGGAC 9731
141 UCCAUCCC A AUAAAAAU 3082 AUUUUUAU CUGAUGAGGCCGUUAGGCCGAA IGGAUGGA 9732
151 UAAAAAUC A GGAGACCC 3083 GGGUCUCC CUGAUGAGGCCGUUAGGCCGAA IAUUUUUA 9733
158 CAGGAGAC C CUGGCUAU 3084 AUAGCCAG CUGAUGAGGCCGUUAGGCCGAA IUCUCCUG 9734
159 AGGAGACC C UGGCUAUC 3085 GAUAGCCA CUGAUGAGGCCGUUAGGCCGAA IGUCUCCU 9735
160 GGAGACCC U GGCUAUCA 3086 UGAUAGCC CUGAUGAGGCCGUUAGGCCGAA IGGUCUCC 9736
164 ACCCUGGC U AUCAUAGA 3087 UCUAUGAU CUGAUGAGGCCGUUAGGCCGAA ICCAGGGU 9737
168 UGGCUAUC A UAGACCUU 3088 AAGGUCUA CUGAUGAGGCCGUUAGGCCGAA IAUAGCCA 9738
174 UCAUAGAC C UUAGUCUU 3089 AAGACUAA CUGAUGAGGCCGUUAGGCCGAA IUCUAUGA 9739
175 CAUAGACC U UAGUCUUC 3090 GAAGACUA CUGAUGAGGCCGUUAGGCCGAA IGUCUAUG 9740
181 CCUUAGUC U UCGCUGGU 3091 ACCAGCGA CUGAUGAGGCCGUUAGGCCGAA IACUAAGG 9741
186 GUCUUCGC U GGUAUACU 3092 AGUAUACC CUGAUGAGGCCGUUAGGCCGAA ICGAAGAC 9742
194 UGGUAUAC U CGCUGUCU 3093 AGACAGCG CUGAUGAGGCCGUUAGGCCGAA IUAUACCA 9743
198 AUACUCGC U GUCUGUCA 3094 UGACAGAC CUGAUGAGGCCGUUAGGCCGAA ICGAGUAU 9744
202 UCGCUGUC U GUCAACCA 3095 UGGUUGAC CUGAUGAGGCCGUUAGGCCGAA IACAGCGA 9745
206 UGUCUGUC A ACCAGCGG 3096 CCGCUGGU CUGAUGAGGCCGUUAGGCCGAA IACAGACA 9746
209 CUGUCAAC C AGCGGUUG 3097 CAACCGCU CUGAUGAGGCCGUUAGGCCGAA IUUGACAG 9747 210 UGUCAACC A GCGGUUGA 3098 UCAACCGC CUGAUGAGGCCGUUAGGCCGAA IGUUGACA 9748
220 CGGUUGAC U UUUUUUAA 3099 UUAAAAAA CUGAUGAGGCCGUUAGGCCGAA IUCAACCG 9749
231 UUUUAAGC C UUCUUUUU 3100 AAAAAGAA CUGAUGAGGCCGUUAGGCCGAA ICUUAAAA 9750
232 UUUAAGCC U UCUUUUUU 3101 AAAAAAGA CUGAUGAGGCCGUUAGGCCGAA IGCUUAAA 9751
235 AAGCCUUC U UUUUUCUC 3102 GAGAAAAA CUGAUGAGGCCGUUAGGCCGAA IAAGGCUU 9752
242 CUUUUUUC U CUUUUACC 3103 GGUAAAAG CUGAUGAGGCCGUUAGGCCGAA IAAAAAAG 9753
244 UUUUUCUC U UUUACCAG 3104 CUGGUAAA CUGAUGAGGCCGUUAGGCCGAA IAGAAAAA 9754
250 UCUUUUAC C AGUUUCUG 3105 CAGAAACU CUGAUGAGGCCGUUAGGCCGAA IUAAAAGA 9755
251 CUUUUACC A GUUUCUGG 3106 CCAGAAAC CUGAUGAGGCCGUUAGGCCGAA IGUAAAAG 9756
257 CCAGUUUC U GGAGCAAA 3107 UUUGCUCC CUGAUGAGGCCGUUAGGCCGAA IAAACUGG 9757
263 UCUGGAGC A AAUUCAGU 3108 ACUGAAUU CUGAUGAGGCCGUUAGGCCGAA ICUCCAGA 9758
269 GCAAAUUC A GUUUGCCU 3109 AGGCAAAC CUGAUGAGGCCGUUAGGCCGAA IAAUUUGC 9759
276 CAGUUUGC C UUCCUGGA 3110 UCCAGGAA CUGAUGAGGCCGUUAGGCCGAA ICAAACUG 9760
277 AGUUUGCC U UCCUGGAU 3111 AUCCAGGA CUGAUGAGGCCGUUAGGCCGAA IGCAAACU 9761
280 UUGCCUUC C UGGAUUUG 3112 CAAAUCCA CUGAUGAGGCCGUUAGGCCGAA IAAGGCAA 9762
281 UGCCUUCC U GGAUUUGU 3113 ACAAAUCC CUGAUGAGGCCGUUAGGCCGAA IGAAGGCA 9763
303 GUAAUGAC C UCAAAACU 3114 AGUUUUGA CUGAUGAGGCCGUUAGGCCGAA IUCAUUAC 9764
304 UAAUGACC U CAAAACUU 3115 AAGUUUUG CUGAUGAGGCCGUUAGGCCGAA IGUCAUUA 9765
306 AUGACCUC A AAACUUUA 3116 UAAAGUUU CUGAUGAGGCCGUUAGGCCGAA IAGGUCAU 9766
311 CUCAAAAC U UUAGCAGU 3117 ACUGCUAA CUGAUGAGGCCGUUAGGCCGAA IUUUUGAG 9767
317 ACUUUAGC A GUUCUUCC 3118 GGAAGAAC CUGAUGAGGCCGUUAGGCCGAA ICUAAAGU 9768
322 AGCAGUUC U UCCAUCUG 3119 CAGAUGGA CUGAUGAGGCCGUUAGGCCGAA IAACUGCU 9769
325 AGUUCUUC C AUCUGACU 3120 AGUCAGAU CUGAUGAGGCCGUUAGGCCGAA IAAGAACU 9770
326 GUUCUUCC A UCUGACUC 3121 GAGUCAGA CUGAUGAGGCCGUUAGGCCGAA IGAAGAAC 9771
329 CUUCCAUC U GACUCAGG 3122 CCUGAGUC CUGAUGAGGCCGUUAGGCCGAA IAUGGAAG 9772
333 CAUCUGAC U CAGGUUUG 3123 CAAACCUG CUGAUGAGGCCGUUAGGCCGAA IUCAGAUG 9773
335 UCUGACUC A GGUUUGCU 3124 AGCAAACC CUGAUGAGGCCGUUAGGCCGAA IAGUCAGA 9774
343 AGGUUUGC U UCUCUGGC 3125 GCCAGAGA CUGAUGAGGCCGUUAGGCCGAA ICAAACCU 9775
346 UUUGCUUC U CUGGCGGU 3126 ACCGCCAG CUGAUGAGGCCGUUAGGCCGAA IAAGCAAA 9776
348 UGCUUCUC U GGCGGUCU 3127 AGACCGCC CUGAUGAGGCCGUUAGGCCGAA IAGAAGCA 9777
356 UGGCGGUC U UCAGAAUC 3128 GAUUCUGA CUGAUGAGGCCGUUAGGCCGAA IACCGCCA 9778
359 CGGUCUUC A GAAUCAAC 3129 GUUGAUUC CUGAUGAGGCCGUUAGGCCGAA IAAGACCG 9779
365 UCAGAAUC A ACAUCCAC 3130 GUGGAUGU CUGAUGAGGCCGUUAGGCCGAA IAUUCUGA 9780
368 GAAUCAAC A UCCACACU 3131 AGUGUGGA CUGAUGAGGCCGUUAGGCCGAA IUUGAUUC 9781
371 UCAACAUC C ACACUUCC 3132 GGAAGUGU CUGAUGAGGCCGUUAGGCCGAA IAUGUUGA 9782
372 CAACAUCC A CACUUCCG 3133 CGGAAGUG CUGAUGAGGCCGUUAGGCCGAA IGAUGUUG 9783
374 ACAUCCAC A CUUCCGUG 3134 CACGGAAG CUGAUGAGGCCGUUAGGCCGAA IUGGAUGU 9784
376 AUCCACAC U UCCGUGAU 3135 AUCACGGA CUGAUGAGGCCGUUAGGCCGAA lUGUGGAU 9785
379 CACACUUC C GUGAUUAU 3136 AUAAUCAC CUGAUGAGGCCGUUAGGCCGAA IAAGUGUG 9786
389 UGAUUAUC U GCGUGCAU 3137 AUGCACGC CUGAUGAGGCCGUUAGGCCGAA IAUAAUCA 9787
396 CUGCGUGC A UUUUGGAC 3138 GUCCAAAA CUGAUGAGGCCGUUAGGCCGAA ICACGCAG 9788
405 UUUUGGAC A AAGCUUCC 3139 GGAAGCUU CUGAUGAGGCCGUUAGGCCGAA IUCCAAAA 9789
410 GACAAAGC U UCCAACCA 3140 UGGUUGGA CUGAUGAGGCCGUUAGGCCGAA ICUUUGUC 9790
413 AAAGCUUC C AACCAGGA 3141 UCCUGGUU CUGAUGAGGCCGUUAGGCCGAA IAAGCUUU 9791
414 AAGCUUCC A ACCAGGAU 3142 AUCCUGGU CUGAUGAGGCCGUUAGGCCGAA IGAAGCUU 9792
417 CUUCCAAC C AGGAUACG 3143 CGUAUCCU CUGAUGAGGCCGUUAGGCCGAA IUUGGAAG 9793
418 UUCCAACC A GGAUACGG 3144 CCGUAUCC CUGAUGAGGCCGUUAGGCCGAA IGUUGGAA 9794
441 GAAAUGGC U GGUGAUCU 3145 AGAUCACC CUGAUGAGGCCGUUAGGCCGAA ICCAUUUC 9795
449 UGGUGAUC U UUCAGCAG 3146 CUGCUGAA CUGAUGAGGCCGUUAGGCCGAA IAUCACCA 9796
453 GAUCUUUC A GCAGGUUU 3147 AAACCUGC CUGAUGAGGCCGUUAGGCCGAA IAAAGAUC 9797
456 CUUUCAGC A GGUUUCUU 3148 AAGAAACC CUGAUGAGGCCGUUAGGCCGAA ICUGAAAG 9798 463 CAGGUUUC U UCAUGGAG 3149 CUCCAUGA CUGAUGAGGCCGUUAGGCCGAA IAAACCUG 9799
466 GUUUCUUC A UGGAGGAA 3150 UUCCUCCA CUGAUGAGGCCGUUAGGCCGAA IAAGAAAC 9800
476 GGAGGAAC U UAAUACAU 3151 AUGUAUUA CUGAUGAGGCCGUUAGGCCGAA IUUCCUCC 9801
483 CUUAAUAC A UACCGUCA 3152 UGACGGUA CUGAUGAGGCCGUUAGGCCGAA IUAUUAAG 9802
487 AUACAUAC C GUCAGAAG 3153 CUUCUGAC CUGAUGAGGCCGUUAGGCCGAA IUAUGUAU 9803
491 AUACCGUC A GAAGCAGG 3154 CCUGCUUC CUGAUGAGGCCGUUAGGCCGAA IACGGUAU 9804
497 UCAGAAGC A GGGAGUAG 3155 CUACUCCC CUGAUGAGGCCGUUAGGCCGAA ICUUCUGA 9805
509 AGUAGUAC U UAAAUAUC 3156 GAUAUUUA CUGAUGAGGCCGUUAGGCCGAA IUACUACU 9806
518 UAAAUAUC A AGAACUGC 3157 GCAGUUCU CUGAUGAGGCCGUUAGGCCGAA IAUAUUUA 9807
524 UCAAGAAC U GCCUAAUU 3158 AAUUAGGC CUGAUGAGGCCGUUAGGCCGAA lUUCUUGA 9808
527 AGAACUGC C UAAUUCAG 3159 CUGAAUUA CUGAUGAGGCCGUUAGGCCGAA ICAGUUCU 9809
528 GAACUGCC U AAUUCAGG 3160 CCUGAAUU CUGAUGAGGCCGUUAGGCCGAA IGCAGUUC 9810
534 CCUAAUUC A GGACCUCC 3161 GGAGGUCC CUGAUGAGGCCGUUAGGCCGAA IAAUUAGG 9811
539 UUCAGGAC C UCCACAUG 3162 CAUGUGGA CUGAUGAGGCCGUUAGGCCGAA IUCCUGAA 9812
540 UCAGGACC U CCACAUGA 3163 UCAUGUGG CUGAUGAGGCCGUUAGGCCGAA IGUCCUGA 9813
542 AGGACCUC C ACAUGAUA 3164 UAUCAUGU CUGAUGAGGCCGUUAGGCCGAA IAGGUCCU 9814
543 GGACCUCC A CAUGAUAG 3165 CUAUCAUG CUGAUGAGGCCGUUAGGCCGAA IGAGGUCC 9815
545 ACCUCCAC A UGAUAGGA 3166 UCCUAUCA CUGAUGAGGCCGUUAGGCCGAA IUGGAGGU 9816
561 AGGUUUAC A UUUCAAGU 3167 ACUUGAAA CUGAUGAGGCCGUUAGGCCGAA IUAAACCU 9817
566 UACAUUUC A AGUUAUAA 3168 UUAUAACU CUGAUGAGGCCGUUAGGCCGAA IAAAUGUA 9818
593 AGAAUUUC C AGAAGGUG 3169 CACCUUCU CUGAUGAGGCCGUUAGGCCGAA IAAAUUCU 9819
594 GAAUUUCC A GAAGGUGA 3170 UCACCUUC CUGAUGAGGCCGUUAGGCCGAA IGAAAUUC 9820
612 GGUAGAUC A AAGAAGGA 3171 UCCUUCUU CUGAUGAGGCCGUUAGGCCGAA IAUCUACC 9821
624 AAGGAAGC A AAAAAUGC 3172 GCAUUUUU CUGAUGAGGCCGUUAGGCCGAA ICUUCCUU 9822
633 AAAAAUGC C GCAGCCAA 3173 UUGGCUGC CUGAUGAGGCCGUUAGGCCGAA ICAUUUUU 9823
636 AAUGCCGC A GCCAAAUU 3174 AAUUUGGC CUGAUGAGGCCGUUAGGCCGAA ICGGCAUU 9824
639 GCCGCAGC C AAAUUAGC 3175 GCUAAUUU CUGAUGAGGCCGUUAGGCCGAA ICUGCGGC 9825
640 CCGCAGCC A AAUUAGCU 3176 AGCUAAUU CUGAUGAGGCCGUUAGGCCGAA IGCUGCGG 9826
648 AAAUUAGC U GUUGAGAU 3177 AUCUCAAC CUGAUGAGGCCGUUAGGCCGAA ICUAAUUU 9827
659 UGAGAUAC U UAAUAAGG 3178 CCUUAUUA CUGAUGAGGCCGUUAGGCCGAA IUAUCUCA 9828
678 AAGAAGGC A GUUAGUCC 3179 GGACUAAC CUGAUGAGGCCGUUAGGCCGAA ICCUUCUU 9829
686 AGUUAGUC C UUUAUUAU 3180 AUAAUAAA CUGAUGAGGCCGUUAGGCCGAA IACUAACU 9830
687 GUUAGUCC U UUAUUAUU 3181 AAUAAUAA CUGAUGAGGCCGUUAGGCCGAA IGACUAAC 9831
699 UUAUUGAC A ACAACGAA 3182 UUCGUUGU CUGAUGAGGCCGUUAGGCCGAA lUCAAUAA 9832
702 UUGACAAC A ACGAAUUC 3183 GAAUUCGU CUGAUGAGGCCGUUAGGCCGAA IUUGUCAA 9833
711 ACGAAUUC U UCAGAAGG 3184 CCUUCUGA CUGAUGAGGCCGUUAGGCCGAA IAAUUCGU 9834
714 AAUUCUUC A GAAGGAUU 3185 AAUCCUUC CUGAUGAGGCCGUUAGGCCGAA IAAGAAUU 9835
726 GGAUUAUC C AUGGGGAA 3186 UUCCCCAU CUGAUGAGGCCGUUAGGCCGAA IAUAAUCC 9836
727 GAUUAUCC A UGGGGAAU 3187 AUUCCCCA CUGAUGAGGCCGUUAGGCCGAA IGAUAAUC 9837
739 GGAAUUAC A UAGGCCUU 3188 AAGGCCUA CUGAUGAGGCCGUUAGGCCGAA IUAAUUCC 9838
745 ACAUAGGC C UUAUCAAU 3189 AUUGAUAA CUGAUGAGGCCGUUAGGCCGAA ICCUAUGU 9839
746 CAUAGGCC U UAUCAAUA 3190 UAUUGAUA CUGAUGAGGCCGUUAGGCCGAA IGCCUAUG 9840
751 GCCUUAUC A AUAGAAUU 3191 AAUUCUAU CUGAUGAGGCCGUUAGGCCGAA IAUAAGGC 9841
762 AGAAUUGC C CAGAAGAA 3192 UUCUUCUG CUGAUGAGGCCGUUAGGCCGAA ICAAUUCU 9842
763 GAAUUGCC C AGAAGAAA 3193 UUUCUUCU CUGAUGAGGCCGUUAGGCCGAA IGCAAUUC 9843
764 AAUUGCCC A GAAGAAAA 3194 UUUUCUUC CUGAUGAGGCCGUUAGGCCGAA IGGCAAUU 9844
776 GAAAAGAC U AACUGUAA 3195 UUACAGUU CUGAUGAGGCCGUUAGGCCGAA IUCUUUUC 9845
780 AGACUAAC U GUAAAUUA 3196 UAAUUUAC CUGAUGAGGCCGUUAGGCCGAA IUUAGUCU 9846
794 UUAUGAAC A GUGUGCAU 3197 AUGCACAC CUGAUGAGGCCGUUAGGCCGAA IUUCAUAA 9847
801 CAGUGUGC A UCGGGGGU 3198 ACCCCCGA CUGAUGAGGCCGUUAGGCCGAA ICACACUG 9848
812 GGGGGUGC A UGGGCCAG 3199 CUGGCCCA CUGAUGAGGCCGUUAGGCCGAA ICACCCCC 9849 818 GCAUGGGC C AGAAGGAU 3200 AUCCUUCU CUGAUGAGGCCGUUAGGCCGAA ICCCAUGC 9850
819 CAUGGGCC A GAAGGAUU 3201 AAUCCUUC CUGAUGAGGCCGUUAGGCCGAA IGCCCAUG 9851
830 AGGAUUUC A UUAUAAAU 3202 AUUUAUAA CUGAUGAGGCCGUUAGGCCGAA IAAAUCCU 9852
841 AUAAAUGC A AAAUGGGA 3203 UCCCAUUU CUGAUGAGGCCGUUAGGCCGAA ICAUUUAU 9853
851 AAUGGGAC A GAAAGAAU 3204 AUUCUUUC CUGAUGAGGCCGUUAGGCCGAA IUCCCAUU 9854
873 AUUGGUAC A GGUUCUAC 3205 GUAGAACC CUGAUGAGGCCGUUAGGCCGAA IUACCAAU 9855
879 ACAGGUUC U ACUAAACA 3206 UGUUUAGU CUGAUGAGGCCGUUAGGCCGAA IAACCUGU 9856
882 GGUUCUAC U AAACAGGA 3207 UCCUGUUU CUGAUGAGGCCGUUAGGCCGAA IUAGAACC 9857
887 UACUAAAC A GGAAGCAA 3208 UUGCUUCC CUGAUGAGGCCGUUAGGCCGAA lUUUAGUA 9858
894 CAGGAAGC A AAACAAUU 3209 AAUUGUUU CUGAUGAGGCCGUUAGGCCGAA ICUUCCUG 9859
899 AGCAAAAC A AUUGGCCG 3210 CGGCCAAU CUGAUGAGGCCGUUAGGCCGAA IUUUUGCU 9860
906 CAAUUGGC C GCUAAACU 3211 AGUUUAGC CUGAUGAGGCCGUUAGGCCGAA ICCAAUUG 9861
909 UUGGCCGC U AAACUUGC 3212 GCAAGUUU CUGAUGAGGCCGUUAGGCCGAA ICGGCCAA 9862
914 CGCUAAAC U UGCAUAUC 3213 GAUAUGCA CUGAUGAGGCCGUUAGGCCGAA IUUUAGCG 9863
918 AAACUUGC A UAUCUUCA 3214 UGAAGAUA CUGAUGAGGCCGUUAGGCCGAA ICAAGUUU 9864
923 UGCAUAUC U UCAGAUAU 3215 AUAUCUGA CUGAUGAGGCCGUUAGGCCGAA IAUAUGCA 9865
926 AUAUCUUC A GAUAUUAU 3216 AUAAUAUC CUGAUGAGGCCGUUAGGCCGAA lAAGAUAU 9866
936 AUAUUAUC A GAAGAAAC 3217 GUUUCUUC CUGAUGAGGCCGUUAGGCCGAA IAUAAUAU 9867
945 GAAGAAAC C UCAGUGAA 3218 UUCACUGA CUGAUGAGGCCGUUAGGCCGAA IUUUCUUC 9868
946 AAGAAACC U CAGUGAAA 3219 UUUCACUG CUGAUGAGGCCGUUAGGCCGAA IGUUUCUU 9869
948 GAAACCUC A GUGAAAUC 3220 GAUUUCAC CUGAUGAGGCCGUUAGGCCGAA IAGGUUUC 9870
957 GUGAAAUC U GACUACCU 3221 AGGUAGUC CUGAUGAGGCCGUUAGGCCGAA IAUUUCAC 9871
961 AAUCUGAC U ACCUGUCC 3222 GGACAGGU CUGAUGAGGCCGUUAGGCCGAA IUCAGAUU 9872
964 CUGACUAC C UGUCCUCU 3223 AGAGGACA CUGAUGAGGCCGUUAGGCCGAA IUAGUCAG 9873
965 UGACUACC U GUCCUCUG 3224 CAGAGGAC CUGAUGAGGCCGUUAGGCCGAA IGUAGUCA 9874
969 UACCUGUC C UCUGGUUC 3225 GAACCAGA CUGAUGAGGCCGUUAGGCCGAA IACAGGUA 9875
970 ACCUGUCC U CUGGUUCU 3226 AGAACCAG CUGAUGAGGCCGUUAGGCCGAA IGACAGGU 9876
972 CUGUCCUC U GGUUCUUU 3227 AAAGAACC CUGAUGAGGCCGUUAGGCCGAA IAGGACAG 9877
978 UCUGGUUC U UUUGCUAC 3228 GUAGCAAA CUGAUGAGGCCGUUAGGCCGAA IAACCAGA 9878
984 UCUUUUGC U ACUACGUG 3229 CACGUAGU CUGAUGAGGCCGUUAGGCCGAA ICAAAAGA 9879
987 UUUGCUAC U ACGUGUGA 3230 UCACACGU CUGAUGAGGCCGUUAGGCCGAA IUAGCAAA 9880
999 UGUGAGUC C CAAAGCAA 3231 UUGCUUUG CUGAUGAGGCCGUUAGGCCGAA IACUCACA 9881
1000 GUGAGUCC C AAAGCAAC 3232 GUUGCUUU CUGAUGAGGCCGUUAGGCCGAA IGACUCAC 9882
1001 UGAGUCCC A AAGCAACU 3233 AGUUGCUU CUGAUGAGGCCGUUAGGCCGAA IGGACUCA 9883
1006 CCCAAAGC A ACUCUUUA 3234 UAAAGAGU CUGAUGAGGCCGUUAGGCCGAA ICUUUGGG 9884
1009 AAAGCAAC U CUUUAGUG 3235 CACUAAAG CUGAUGAGGCCGUUAGGCCGAA IUUGCUUU 9885
1011 AGCAACUC U UUAGUGAC 3236 GUCACUAA CUGAUGAGGCCGUUAGGCCGAA IAGUUGCU 9886
1020 UUAGUGAC C AGCACACU 3237 AGUGUGCU CUGAUGAGGCCGUUAGGCCGAA lUCACUAA 9887
1021 UAGUGACC A GCACACUC 3238 GAGUGUGC CUGAUGAGGCCGUUAGGCCGAA IGUCACUA 9888
1024 UGACCAGC A CACUCGCU 3239 AGCGAGUG CUGAUGAGGCCGUUAGGCCGAA ICUGGUCA 9889
1026 ACCAGCAC A CUCGCUUC 3240 GAAGCGAG CUGAUGAGGCCGUUAGGCCGAA IUGCUGGU 9890
1028 CAGCACAC U CGCUUCUG 3241 CAGAAGCG CUGAUGAGGCCGUUAGGCCGAA IUGUGCUG 9891
1032 ACACUCGC U UCUGAAUC 3242 GAUUCAGA CUGAUGAGGCCGUUAGGCCGAA ICGAGUGU 9892
1035 CUCGCUUC U GAAUCAUC 3243 GAUGAUUC CUGAUGAGGCCGUUAGGCCGAA IAAGCGAG 9893
1041 UCUGAAUC A UCAUCUGA 3244 UCAGAUGA CUGAUGAGGCCGUUAGGCCGAA IAUUCAGA 9894
1044 GAAUCAUC A UCUGAAGG 3245 CCUUCAGA CUGAUGAGGCCGUUAGGCCGAA IAUGAUUC 9895
1047 UCAUCAUC U GAAGGUGA 3246 UCACCUUC CUGAUGAGGCCGUUAGGCCGAA IAUGAUGA 9896
1057 AAGGUGAC U UCUCAGCA 3247 UGCUGAGA CUGAUGAGGCCGUUAGGCCGAA IUCACCUU 9897
1060 GUGACUUC U CAGCAGAU 3248 AUCUGCUG CUGAUGAGGCCGUUAGGCCGAA IAAGUCAC 9898
1062 GACUUCUC A GCAGAUAC 3249 GUAUCUGC CUGAUGAGGCCGUUAGGCCGAA IAGAAGUC 9899
1065 UUCUCAGC A GAUACAUC 3250 GAUGUAUC CUGAUGAGGCCGUUAGGCCGAA ICUGAGAA 9900 1071 GCAGAUAC A UCAGAGAU 3251 AUCUCUGA CUGAUGAGGCCGUUAGGCCGAA IUAUCUGC 9901
1074 GAUACAUC A GAGAUAAA 3252 UUUAUCUC CUGAUGAGGCCGUUAGGCCGAA IAUGUAUC 9902
1086 AUAAAUUC U AACAGUGA 3253 UCACUGUU CUGAUGAGGCCGUUAGGCCGAA IAAUUUAU 9903
1090 AUUCUAAC A GUGACAGU 3254 ACUGUCAC CUGAUGAGGCCGUUAGGCCGAA IUUAGAAU 9904
1096 ACAGUGAC A GUUUAAAC 3255 GUUUAAAC CUGAUGAGGCCGUUAGGCCGAA IUCACUGU 9905
1105 GUUUAAAC A GUUCUUCG 3256 CGAAGAAC CUGAUGAGGCCGUUAGGCCGAA IUUUAAAC 9906
1110 AACAGUUC U UCGUUGCU 3257 AGCAACGA CUGAUGAGGCCGUUAGGCCGAA IAACUGUU 9907
1118 UUCGUUGC U UAUGAAUG 3258 CAUUCAUA CUGAUGAGGCCGUUAGGCCGAA ICAACGAA 9908
1130 GAAUGGUC U CAGAAAUA 3259 UAUUUCUG CUGAUGAGGCCGUUAGGCCGAA IACCAUUC 9909
1132 AUGGUCUC A GAAAUAAU 3260 AUUAUUUC CUGAUGAGGCCGUUAGGCCGAA IAGACCAU 9910
1142 AAAUAAUC A AAGGAAGG 3261 CCUUCCUU CUGAUGAGGCCGUUAGGCCGAA IAUUAUUU 9911
1152 AGGAAGGC A AAAAGAUC 3262 GAUCUUUU CUGAUGAGGCCGUUAGGCCGAA ICCUUCCU 9912
1161 AAAAGAUC U UUGGCACC 3263 GGUGCCAA CUGAUGAGGCCGUUAGGCCGAA IAUCUUUU 9913
1167 UCUUUGGC A CCCAGAUU 3264 AAUCUGGG CUGAUGAGGCCGUUAGGCCGAA ICCAAAGA 9914
1169 UUUGGCAC C CAGAUUUG 3265 CAAAUCUG CUGAUGAGGCCGUUAGGCCGAA IUGCCAAA 9915
1170 UUGGCACC C AGAUUUGA 3266 UCAAAUCU CUGAUGAGGCCGUUAGGCCGAA IGUGCCAA 9916
1171 UGGCACCC A GAUUUGAC 3267 GUGAAAUC CUGAUGAGGCCGUUAGGCCGAA IGGUGCCA 9917
1180 GAUUUGAC C UUCCUGAC 3268 GUCAGGAA CUGAUGAGGCCGUUAGGCCGAA IUCAAAUC 9918
1181 AUUUGACC U UCCUGACA 3269 UGUCAGGA CUGAUGAGGCCGUUAGGCCGAA IGUCAAAU 9919
1184 UGACCUUC C UGACAUGA 3270 UCAUGUCA CUGAUGAGGCCGUUAGGCCGAA IAAGGUCA 9920
1185 GACCUUCC U GACAUGAA 3271 UUCAUGUC CUGAUGAGGCCGUUAGGCCGAA IGAAGGUC 9921
1189 UUCCUGAC A UGAAAGAA 3272 UUCUUUCA CUGAUGAGGCCGUUAGGCCGAA IUCAGGAA 9922
1200 AAAGAAAC A AAGUAUAC 3273 GUAUACUU CUGAUGAGGCCGUUAGGCCGAA IUUUCUUU 9923
1209 AAGUAUAC U GUGGACAA 3274 UUGUCCAC CUGAUGAGGCCGUUAGGCCGAA IUAUACUU 9924
1216 CUGUGGAC A AGAGGUUU 3275 AAACCUCU CUGAUGAGGCCGUUAGGCCGAA IUCCACAG 9925
1228 GGUUUGGC A UGGAUUUU 3276 AAAAUCCA CUGAUGAGGCCGUUAGGCCGAA ICCAAACC 9926
1258 UAAUUGGC U CAGGUGGA 3277 UCCACCUG CUGAUGAGGCCGUUAGGCCGAA ICCAAUUA 9927
1260 AUUGGCUC A GGUGGAUU 3278 AAUCCACC CUGAUGAGGCCGUUAGGCCGAA lAGCCAAU 9928
1273 GAUUUGGC C AAGUUUUC 3279 GAAAACUU CUGAUGAGGCCGUUAGGCCGAA ICCAAAUC 9929
1274 AUUUGGCC A AGUUUUCA 3280 UGAAAACU CUGAUGAGGCCGUUAGGCCGAA IGCCAAAU 9930
1282 AAGUUUUC A AAGCAAAA 3281 UUUUGCUU CUGAUGAGGCCGUUAGGCCGAA IAAAACUU 9931
1287 UUCAAAGC A AAACACAG 3282 CUGUGUUU CUGAUGAGGCCGUUAGGCCGAA ICUUUGAA 9932
1292 AGCAAAAC A CAGAAUUG 3283 CAAUUCUG CUGAUGAGGCCGUUAGGCCGAA IUUUUGCU 9933
1294 CAAAACAC A GAAUUGAC 3284 GUCAAUUC CUGAUGAGGCCGUUAGGCCGAA IUGUUUUG 9934
1311 GGAAAGAC U UACGUUAU 3285 AUAACGUA CUGAUGAGGCCGUUAGGCCGAA IUCUUUCC 9935
1368 GUAAAAGC A UUGGCAAA 3286 UUUGCCAA CUGAUGAGGCCGUUAGGCCGAA ICUUUUAC 9936
1374 GCAUUGGC A AAACUUGA 3287 UCAAGUUU CUGAUGAGGCCGUUAGGCCGAA ICCAAUGC 9937
1379 GGCAAAAC U UGAUCAUG 3288 CAUGAUCA CUGAUGAGGCCGUUAGGCCGAA IUUUUGCC 9938
1385 ACUUGAUC A UGUAAAUA 3289 UAUUUACA CUGAUGAGGCCGUUAGGCCGAA IAUCAAGU 9939
1400 UAUUGUUC A CUACAAUG 3290 CAUUGUAG CUGAUGAGGCCGUUAGGCCGAA IAACAAUA 9940
1402 UUGUUCAC U ACAAUGGC 3291 GCCAUUGU CUGAUGAGGCCGUUAGGCCGAA IUGAACAA 9941
1405 UUCACUAC A AUGGCUGU 3292 ACAGCCAU CUGAUGAGGCCGUUAGGCCGAA lUAGUGAA 9942
1411 ACAAUGGC U GUUGGGAU 3293 AUCCCAAC CUGAUGAGGCCGUUAGGCCGAA ICCAUUGU 9943
1436 UUAUGAUC C UGAGACCA 3294 UGGUCUCA CUGAUGAGGCCGUUAGGCCGAA IAUCAUAA 9944
1437 UAUGAUCC U GAGACCAG 3295 CUGGUCUC CUGAUGAGGCCGUUAGGCCGAA IGAUCAUA 9945
1443 CCUGAGAC C AGUGAUGA 3296 UCAUCACU CUGAUGAGGCCGUUAGGCCGAA IUCUCAGG 9946
1444 CUGAGACC A GUGAUGAU 3297 AUCAUCAC CUGAUGAGGCCGUUAGGCCGAA IGUCUCAG 9947
1455 GAUGAUUC U CUUGAGAG 3298 CUCUCAAG CUGAUGAGGCCGUUAGGCCGAA IAAUCAUC 9948
1457 UGAUUCUC U UGAGAGCA 3299 UGCUCUCA CUGAUGAGGCCGUUAGGCCGAA IAGAAUCA 9949
1465 UUGAGAGC A GUGAUUAU 3300 AUAAUCAC CUGAUGAGGCCGUUAGGCCGAA ICUCUCAA 9950
1478 UUAUGAUC C UGAGAACA 3301 UGUUCUCA CUGAUGAGGCCGUUAGGCCGAA IAUCAUAA 9951 1479 UAUGAUCC U GAGAACAG 3302 CUGUUCUC CUGAUGAGGCCGUUAGGCCGAA IGAUCAUA 9952
1486 CUGAGAAC A GCAAAAAU 3303 AUUUUUGC CUGAUGAGGCCGUUAGGCCGAA IUUCUCAG 9953
1489 AGAACAGC A AAAAUAGU 3304 ACUAUUUU CUGAUGAGGCCGUUAGGCCGAA ICUGUUCU 9954
1500 AAUAGUUC A AGGUCAAA 3305 UUUGACCU CUGAUGAGGCCGUUAGGCCGAA IAACUAUU 9955
1506 UCAAGGUC A AAGACUAA 3306 UUAGUCUU CUGAUGAGGCCGUUAGGCCGAA IACCUUGA 9956
1512 UCAAAGAC U AAGUGCCU 3307 AGGCACUU CUGAUGAGGCCGUUAGGCCGAA IUCUUUGA 9957
1519 CUAAGUGC C UUUUCAUC 3308 GAUGAAAA CUGAUGAGGCCGUUAGGCCGAA ICACUUAG 9958
1520 UAAGUGCC U UUUCAUCC 3309 GGAUGAAA CUGAUGAGGCCGUUAGGCCGAA IGCACUUA 9959
1525 GCCUUUUC A UCCAAAUG 3310 CAUUUGGA CUGAUGAGGCCGUUAGGCCGAA IAAAAGGC 9960
1528 UUUUCAUC C AAAUGGAA 3311 UUCCAUUU CUGAUGAGGCCGUUAGGCCGAA IAUGAAAA 9961
1529 UUUCAUCC A AAUGGAAU 3312 AUUCCAUU CUGAUGAGGCCGUUAGGCCGAA IGAUGAAA 9962
1540 UGGAAUUC U GUGAUAAA 3313 UUUAUCAC CUGAUGAGGCCGUUAGGCCGAA IAAUUCCA 9963
1554 AAAGGGAC C UUGGAACA 3314 UGUUCCAA CUGAUGAGGCCGUUAGGCCGAA IUCCCUUU 9964
1555 AAGGGACC U UGGAACAA 3315 UUGUUCCA CUGAUGAGGCCGUUAGGCCGAA IGUCCCUU 9965
1562 CUUGGAAC A AUGGAUUG 3316 CAAUCCAU CUGAUGAGGCCGUUAGGCCGAA IUUCCAAG 9966
1592 CGAGAAAC U AGACAAAG 3317 CUUUGUCU CUGAUGAGGCCGUUAGGCCGAA IUUUCUCG 9967
1597 AACUAGAC A AAGUUUUG 3318 CAAAACUU CUGAUGAGGCCGUUAGGCCGAA IUCUAGUU 9968
1608 GUUUUGGC U UUGGAACU 3319 AGUUCCAA CUGAUGAGGCCGUUAGGCCGAA ICCAAAAC 9969
1616 UUUGGAAC U CUUUGAAC 3320 GUUCAAAG CUGAUGAGGCCGUUAGGCCGAA IUUCCAAA 9970
1618 UGGAACUC U UUGAACAA 3321 UUGUUCAA CUGAUGAGGCCGUUAGGCCGAA IAGUUCCA 9971
1625 CUUUGAAC A AAUAACAA 3322 UUGUUAUU CUGAUGAGGCCGUUAGGCCGAA IUUCAAAG 9972
1632 CAAAUAAC A AAAGGGGU 3323 ACCCCUUU CUGAUGAGGCCGUUAGGCCGAA IUUAUUUG 9973
1652 UUAUAUAC A UUCAAAAA 3324 UUUUUGAA CUGAUGAGGCCGUUAGGCCGAA IUAUAUAA 9974
1656 AUACAUUC A AAAAAAUU 3325 AAUUUUUU CUGAUGAGGCCGUUAGGCCGAA IAAUGUAU 9975
1670 AUUAAUUC A UAGAGAUC 3326 GAUCUCUA CUGAUGAGGCCGUUAGGCCGAA IAAUUAAU 9976
1679 UAGAGAUC U UAAGCCAA 3327 UUGGCUUA CUGAUGAGGCCGUUAGGCCGAA lAUCUCUA 9977
1685 UCUUAAGC C AAGUAAUA 3328 UAUUACUU CUGAUGAGGCCGUUAGGCCGAA ICUUAAGA 9978
1686 CUUAAGCC A AGUAAUAU 3329 AUAUUACU CUGAUGAGGCCGUUAGGCCGAA IGCUUAAG 9979
1699 AUAUAUUC U UAGUAGAU 3330 AUCUACUA CUGAUGAGGCCGUUAGGCCGAA IAAUAUAU 9980
1710 GUAGAUAC A AAACAAGU 3331 ACUUGUUU CUGAUGAGGCCGUUAGGCCGAA IUAUCUAC 9981
1715 UACAAAAC A AGUAAAGA 3332 UCUUUACU CUGAUGAGGCCGUUAGGCCGAA IUUUUGUA 9982
1732 UUGGAGAC U UUGGACUU 3333 AAGUCCAA CUGAUGAGGCCGUUAGGCCGAA IUCUCCAA 9983
1739 CUUUGGAC U UGUAACAU 3334 AUGUUACA CUGAUGAGGCCGUUAGGCCGAA IUCCAAAG 9984
1746 CUUGUAAC A UCUCUGAA 3335 UUCAGAGA CUGAUGAGGCCGUUAGGCCGAA IUUACAAG 9985
1749 GUAACAUC U CUGAAAAA 3336 UUUUUCAG CUGAUGAGGCCGUUAGGCCGAA IAUGUUAC 9986
1751 AACAUCUC U GAAAAAUG 3337 CAUUUUUC CUGAUGAGGCCGUUAGGCCGAA IAGAUGUU 9987
1773 AAGCGAAC A AGGAGUAA 3338 UUACUCCU CUGAUGAGGCCGUUAGGCCGAA IUUCGCUU 9988
1788 AAGGGAAC U UUGCGAUA 3339 UAUCGCAA CUGAUGAGGCCGUUAGGCCGAA IUUCCCUU 9989
1798 UGCGAUAC A UGAGCCCA 3340 UGGGCUCA CUGAUGAGGCCGUUAGGCCGAA IUAUCGCA 9990
1804 ACAUGAGC C CAGAACAG 3341 CUGUUCUG CUGAUGAGGCCGUUAGGCCGAA ICUCAUGU 9991
1805 CAUGAGCC C AGAACAGA 3342 UCUGUUCU CUGAUGAGGCCGUUAGGCCGAA IGCUCAUG 9992
1806 AUGAGCCC A GAACAGAU 3343 AUCUGUUC CUGAUGAGGCCGUUAGGCCGAA IGGCUCAU 9993
1811 CCCAGAAC A GAUUUCUU 3344 AAGAAAUC CUGAUGAGGCCGUUAGGCCGAA IUUCUGGG 9994
1818 CAGAUUUC U UCGCAAGA 3345 UCUUGCGA CUGAUGAGGCCGUUAGGCCGAA IAAAUCUG 9995
1823 UUCUUCGC A AGACUAUG 3346 CAUAGUCU CUGAUGAGGCCGUUAGGCCGAA ICGAAGAA 9996
1828 CGCAAGAC U AUGGAAAG 3347 CUUUCCAU CUGAUGAGGCCGUUAGGCCGAA IUCUUGCG 9997
1846 AAGUGGAC C UCUACGCU 3348 AGCGUAGA CUGAUGAGGCCGUUAGGCCGAA IUCCACUU 9998
1847 AGUGGACC U CUACGCUU 3349 AAGCGUAG CUGAUGAGGCCGUUAGGCCGAA IGUCCACU 9999
1849 UGGACCUC U ACGCUUUG 3350 CAAAGCGU CUGAUGAGGCCGUUAGGCCGAA IAGGUCCA 10000
1854 CUCUACGC U UUGGGGCU 3351 AGCCCCAA CUGAUGAGGCCGUUAGGCCGAA ICGUAGAG 10001
1862 UUUGGGGC U AAUUCUUG 3352 CAAGAAUU CUGAUGAGGCCGUUAGGCCGAA ICCCCAAA 10002 1868 GCUAAUUC U UGCUGAAC 3353 GUUCAGCA CUGAUGAGGCCGUUAGGCCGAA IAAUUAGC 10003
1872 AUUCUUGC U GAACUUCU 3354 AGAAGUUC CUGAUGAGGCCGUUAGGCCGAA ICAAGAAU 10004
1877 UGCUGAAC U UCUUGAUG 3355 CAUGAAGA CUGAUGAGGCCGUUAGGCCGAA IUUCAGCA 10005
1880 UGAACUUC U UCAUGUAU 3356 AUACAUGA CUGAUGAGGCCGUUAGGCCGAA lAAGUUCA 10006
1883 ACUUCUUC A UGUAUGUG 3357 CAGAUACA CUGAUGAGGCCGUUAGGCCGAA IAAGAAGU 10007
1894 UAUGUGAC A CUGCUUUU 3358 AAAAGCAG CUGAUGAGGCCGUUAGGCCGAA IUCACAUA 10008
1896 UGUGACAC U GCUUUUGA 3359 UCAAAAGC CUGAUGAGGCCGUUAGGCCGAA IUGUCACA 10009
1899 GACACUGC U UUUGAAAC 3360 GUUUCAAA CUGAUGAGGCCGUUAGGCCGAA ICAGUGUC 10010
1908 UUUGAAAC A UCAAAGUU 3361 AACUUUGA CUGAUGAGGCCGUUAGGCCGAA IUUUCAAA 10011
1911 GAAACAUC A AAGUUUUU 3362 AAAAACUU CUGAUGAGGCCGUUAGGCCGAA IAUGUUUC 10012
1921 AGUUUUUC A CAGACCUA 3363 UAGGUCUG CUGAUGAGGCCGUUAGGCCGAA IAAAAACU 10013
1923 UUUUUCAC A GACCUACG 3364 CGUAGGUC CUGAUGAGGCCGUUAGGCCGAA IUGAAAAA 10014
1927 UCACAGAC C UACGGGAU 3365 AUCCCGUA CUGAUGAGGCCGUUAGGCCGAA IUCUGUGA 10015
1928 CACAGACC U ACGGGAUG 3366 CAUCCCGU CUGAUGAGGCCGUUAGGCCGAA IGUCUGUG 10016
1939 GGGAUGGC A UCAUCUCA 3367 UGAGAUGA CUGAUGAGGCCGUUAGGCCGAA ICCAUCCC 10017
1942 AUGGCAUC A UCUCAGAU 3368 AUCUGAGA CUGAUGAGGCCGUUAGGCCGAA IAUGCCAU 10018
1945 GCAUCAUC U CAGAUAUA 3369 UAUAUCUG CUGAUGAGGCCGUUAGGCCGAA IAUGAUGC 10019
1947 AUCAUCUC A GAUAUAUU 3370 AAUAUAUC CUGAUGAGGCCGUUAGGCCGAA IAGAUGAU 10020
1974 GAAAAAAC U CUUCUACA 3371 UGUAGAAG CUGAUGAGGCCGUUAGGCCGAA IUUUUUUC 10021
1976 AAAAACUC U UCUACAGA 3372 UCUGUAGA CUGAUGAGGCCGUUAGGCCGAA IAGUUUUU 10022
1979 AACUCUUC U ACAGAAAU 3373 AUUUCUGU CUGAUGAGGCCGUUAGGCCGAA IAAGAGUU 10023
1982 UCUUCUAC A GAAAUUAC 3374 GUAAUUUC CUGAUGAGGCCGUUAGGCCGAA IUAGAAGA 10024
1991 GAAAUUAC U CUCAAAGA 3375 UCUUUGAG CUGAUGAGGCCGUUAGGCCGAA IUAAUUUC 10025
1993 AAUUACUC U CAAAGAAA 3376 UUUCUUUG CUGAUGAGGCCGUUAGGCCGAA IAGUAAUU 10026
1995 UUACUCUC A AAGAAACC 3377 GGUUUCUU CUGAUGAGGCCGUUAGGCCGAA IAGAGUAA 10027
2003 AAAGAAAC C UGAGGAUC 3378 GAUCCUCA CUGAUGAGGCCGUUAGGCCGAA IUUUCUUU 10028
2004 AAGAAACC U GAGGAUCG 3379 CGAUCCUC CUGAUGAGGCCGUUAGGCCGAA IGUUUCUU 10029
2015 GGAUCGAC C UAACACAU 3380 AUGUGUUA CUGAUGAGGCCGUUAGGCCGAA IUCGAUCC 10030
2016 GAUCGACC U AACACAUC 3381 GAUGUGUU CUGAUGAGGCCGUUAGGCCGAA IGUCGAUC 10031
2020 GACCUAAC A CAUCUGAA 3382 UUCAGAUG CUGAUGAGGCCGUUAGGCCGAA IUUAGGUC 10032
2022 CCUAACAC A UCUGAAAU 3383 AUUUCAGA CUGAUGAGGCCGUUAGGCCGAA IUGUUAGG 10033
2025 AACACAUC U GAAAUACU 3384 AGUAUUUC CUGAUGAGGCCGUUAGGCCGAA IAUGUGUU 10034
2033 UGAAAUAC U AAGGACCU 3385 AGGUCCUU CUGAUGAGGCCGUUAGGCCGAA IUAUUUCA 10035
2040 CUAAGGAC C UUGACUGU 3386 ACAGUCAA CUGAUGAGGCCGUUAGGCCGAA IUCCUUAG 10036
2041 UAAGGACC U UGACUGUG 3387 CACAGUCA CUGAUGAGGCCGUUAGGCCGAA IGUCCUUA 10037
2046 ACCUUGAC U GUGUGGAA 3388 UUCCACAC CUGAUGAGGCCGUUAGGCCGAA IUCAAGGU 10038
2062 AGAAAAGC C CAGAGAAA 3389 UUUCUCUG CUGAUGAGGCCGUUAGGCCGAA ICUUUUCU 10039
2063 GAAAAGCC C AGAGAAAA 3390 UUUUCUCU CUGAUGAGGCCGUUAGGCCGAA IGCUUUUC 10040
2064 AAAAGCCC A GAGAAAAA 3391 UUUUUCUC CUGAUGAGGCCGUUAGGCCGAA IGGCUUUU 10041
2081 UGAACGAC A CACAUGUU 3392 AACAUGUG CUGAUGAGGCCGUUAGGCCGAA lUCGUUCA 10042
2083 AACGACAC A CAUGUUAG 3393 CUAACAUG CUGAUGAGGCCGUUAGGCCGAA IUGUCGUU 10043
2085 CGACACAC A UGUUAGAG 3394 CUCUAACA CUGAUGAGGCCGUUAGGCCGAA IUGUGUCG 10044
2095 GUUAGAGC C CUUCUGAA 3395 UUCAGAAG CUGAUGAGGCCGUUAGGCCGAA ICUCUAAC 10045
2096 UUAGAGCC C UUCUGAAA 3396 UUUCAGAA CUGAUGAGGCCGUUAGGCCGAA IGCUCUAA 10046
2097 UAGAGCCC U UCUGAAAA 3397 UUUUCAGA CUGAUGAGGCCGUUAGGCCGAA IGGCUCUA 10047
2100 AGCCCUUC U GAAAAAGU 3398 ACUUUUUC CUGAUGAGGCCGUUAGGCCGAA IAAGGGCU 10048
2112 AAAGUAUC C UGCUUCUG 3399 CAGAAGCA CUGAUGAGGCCGUUAGGCCGAA IAUACUUU 10049
2113 AAGUAUCC U GCUUCUGA 3400 UCAGAAGC CUGAUGAGGCCGUUAGGCCGAA IGAUACUU 10050
2116 UAUCCUGC U UCUGAUAU 3401 AUAUCAGA CUGAUGAGGCCGUUAGGCCGAA ICAGGAUA 10051
2119 CCUGCUUC U GAUAUGCA 3402 UGCAUAUC CUGAUGAGGCCGUUAGGCCGAA IAAGCAGG 10052
2127 UGAUAUGC A GUUUUCCU 3403 AGGAAAAC CUGAUGAGGCCGUUAGGCCGAA ICAUAUCA 10053 2134 CAGUUUUC C UUAAAUUA 3404 UAAUUUAA CUGAUGAGGCCGUUAGGCCGAA IAAAACUG 10054
2135 AGUUUUCC U UAAAUUAU 3405 AUAAUUUA CUGAUGAGGCCGUUAGGCCGAA IGAAAACU 10055
2145 AAAUUAUC U AAAAUCUG 3406 CAGAUUUU CUGAUGAGGCCGUUAGGCCGAA IAUAAUUU 10056
2152 CUAAAAUC U GCUAGGGA 3407 UCCCUAGC CUGAUGAGGCCGUUAGGCCGAA IAUUUUAG 10057
2155 AAAUCUGC U AGGGAAUA 3408 UAUUCCCU CUGAUGAGGCCGUUAGGCCGAA ICAGAUUU 10058
2166 GGAAUAUC A AUAGAUAU 3409 AUAUCUAU CUGAUGAGGCCGUUAGGCCGAA IAUAUUCC 10059
2179 AUAUUUAC C UUUUAUUU 3410 AAAUAAAA CUGAUGAGGCCGUUAGGCCGAA IUAAAUAU 10060
2180 UAUUUACC U UUUAUUUU 3411 AAAAUAAA CUGAUGAGGCCGUUAGGCCGAA IGUAAAUA 10061
2197 AAUGUUUC C UUUAAUUU 3412 AAAUUAAA CUGAUGAGGCCGUUAGGCCGAA lAAACAUU 10062
2198 AUGUUUCC U UUAAUUUU 3413 AAAAUUAA CUGAUGAGGCCGUUAGGCCGAA IGAAACAU 10063
2211 UUUUUUAC U AUUUUUAC 3414 GUAAAAAU CUGAUGAGGCCGUUAGGCCGAA IUAAAAAA 10064
2220 AUUUUUAC U AAUCUUUC 3415 GAAAGAUU CUGAUGAGGCCGUUAGGCCGAA IUAAAAAU 10065
2225 UACUAAUC U UUCUGCAG 3416 CUGCAGAA CUGAUGAGGCCGUUAGGCCGAA IAUUAGUA 10066
2229 AAUCUUUC U GCAGAAAC 3417 GUUUCUGC CUGAUGAGGCCGUUAGGCCGAA IAAAGAUU 10067
2232 CUUUCUGC A GAAACAGA 3418 UCUGUUUC CUGAUGAGGCCGUUAGGCCGAA ICAGAAAG 10068
2238 GCAGAAAC A GAAAGGUU 3419 AACCUUUC CUGAUGAGGCCGUUAGGCCGAA IUUUCUGC 10069
2250 AGGUUUUC U UCUUUUUG 3420 CAAAAAGA CUGAUGAGGCCGUUAGGCCGAA IAAAACCU 10070
2253 UUUUCUUC U UUUUGCUU 3421 AAGCAAAA CUGAUGAGGCCGUUAGGCCGAA IAAGAAAA 10071
2260 CUUUUUGC U UCAAAAAC 3422 GUUUUUGA CUGAUGAGGCCGUUAGGCCGAA ICAAAAAG 10072
2263 UUUGCUUC A AAAACAUU 3423 AAUGUUUU CUGAUGAGGCCGUUAGGCCGAA IAAGCAAA 10073
2269 UCAAAAAC A UUCUUACA 3424 UGUAAGAA CUGAUGAGGCCGUUAGGCCGAA IUUUUUGA 10074
2273 AAACAUUC U UACAUUUU 3425 AAAAUGUA CUGAUGAGGCCGUUAGGCCGAA IAAUGUUU 10075
2277 AUUCUUAC A UUUUACUU 3426 AAGUAAAA CUGAUGAGGCCGUUAGGCCGAA IUAAGAAU 10076
2284 CAUUUUAC U UUUUCCUG 3427 CAGGAAAA CUGAUGAGGCCGUUAGGCCGAA IUAAAAUG 10077
2290 ACUUUUUC C UGGCUCAU 3428 AUGAGCCA CUGAUGAGGCCGUUAGGCCGAA IAAAAAGU 10078
2291 CUUUUUCC U GGCUCAUC 3429 GAUGAGCC CUGAUGAGGCCGUUAGGCCGAA IGAAAAAG 10079
2295 UUCCUGGC U CAUCUCUU 3430 AAGAGAUG CUGAUGAGGCCGUUAGGCCGAA ICCAGGAA 10080
2297 CCUGGCUC A UCUCUUUA 3431 UAAAGAGA CUGAUGAGGCCGUUAGGCCGAA IAGCCAGG 10081
2300 GGCUCAUC U CUUUAUUC 3432 GAAUAAAG CUGAUGAGGCCGUUAGGCCGAA IAUGAGCC 10082
2302 CUCAUCUC U UUAUUCUU 3433 AAGAAUAA CUGAUGAGGCCGUUAGGCCGAA IAGAUGAG 10083
2309 CUUUAUUC U UUUUUUUU 3434 AAAAAAAA CUGAUGAGGCCGUUAGGCCGAA IAAUAAAG 10084
2329 UUAAAGAC A GAGUCUCG 3435 CGAGACUC CUGAUGAGGCCGUUAGGCCGAA IUCUUUAA 10085
2335 ACAGAGUC U CGCUCUGU 3436 ACAGAGCG CUGAUGAGGCCGUUAGGCCGAA IACUCUGU 10086
2339 AGUCUCGC U CUGUUGCC 3437 GGCAACAG CUGAUGAGGCCGUUAGGCCGAA ICGAGACU 10087
2341 UCUCGCUC U GUUGCCCA 3438 UGGGCAAC CUGAUGAGGCCGUUAGGCCGAA IAGCGAGA 10088
2347 UCUGUUGC C CAGGCUGG 3439 CCAGCCUG CUGAUGAGGCCGUUAGGCCGAA ICAACAGA 10089
2348 CUGUUGCC c AGGCUGGA 3440 UCCAGCCU CUGAUGAGGCCGUUAGGCCGAA IGCAACAG 10090
2349 UGUUGCCC A GGCUGGAG 3441 CUCCAGCC CUGAUGAGGCCGUUAGGCCGAA IGGCAACA 10091
2353 GCCCAGGC U GGAGUGCA 3442 UGCACUCC CUGAUGAGGCCGUUAGGCCGAA ICCUGGGC 10092
2361 UGGAGUGC A AUGACACA 3443 UGUGUCAU CUGAUGAGGCCGUUAGGCCGAA ICACUCCA 10093
2367 GCAAUGAC A CAGUCUUG 3444 CAAGACUG CUGAUGAGGCCGUUAGGCCGAA IUCAUUGC 10094
2369 AAUGACAC A GUCUUGGC 3445 GCCAAGAC CUGAUGAGGCCGUUAGGCCGAA IUGUCAUU 10095
2373 ACACAGUC U UGGCUCAC 3446 GUGAGCCA CUGAUGAGGCCGUUAGGCCGAA IACUGUGU 10096
2378 GUCUUGGC U CACUGCAA 3447 UUGCAGUG CUGAUGAGGCCGUUAGGCCGAA ICCAAGAC 10097
2380 CUUGGCUC A CUGCAACU 3448 AGUUGCAG CUGAUGAGGCCGUUAGGCCGAA IAGCCAAG 10098
2382 UGGCUCAC U GCAACUUC 3449 GAAGUUGC CUGAUGAGGCCGUUAGGCCGAA IUGAGCCA 10099
2385 CUCACUGC A ACUUCUGC 3450 GCAGAAGU CUGAUGAGGCCGUUAGGCCGAA ICAGUGAG 10100
2388 ACUGCAAC U UCUGCCUC 3451 GAGGCAGA CUGAUGAGGCCGUUAGGCCGAA IUUGCAGU 10101
2391 GCAACUUC U GCCUCUUG 3452 CAAGAGGC CUGAUGAGGCCGUUAGGCCGAA IAAGUUGC 10102
2394 ACUUCUGC C UCUUGGGU 3453 ACCCAAGA CUGAUGAGGCCGUUAGGCCGAA ICAGAAGU 10103
2395 CUUCUGCC U CUUGGGUU 3454 AACCCAAG CUGAUGAGGCCGUUAGGCCGAA IGCAGAAG 10104 2397 UCUGCCUC U UGGGUUCA 3455 UGAACCCA CUGAUGAGGCCGUUAGGCCGAA lAGGCAGA 10105
2405 UUGGGUUC A AGUGAUUC 3456 GAAUCACU CUGAUGAGGCCGUUAGGCCGAA IAACCCAA 10106
2414 AGUGAUUC U CCUGCCUC 3457 GAGGCAGG CUGAUGAGGCCGUUAGGCCGAA IAAUCACU 10107
2416 UGAUUCUC C UGCCUCAG 3458 CUGAGGCA CUGAUGAGGCCGUUAGGCCGAA IAGAAUCA 10108
2417 GAUUCUCC U GCCUCAGC 3459 GCUGAGGC CUGAUGAGGCCGUUAGGCCGAA IGAGAAUC 10109
2420 UCUCCUGC C UCAGCCUC 3460 GAGGCUGA CUGAUGAGGCCGUUAGGCCGAA ICAGGAGA 10110
2421 CUCCUGCC U CAGCCUCC 3461 GGAGGCUG CUGAUGAGGCCGUUAGGCCGAA IGCAGGAG 10111
2423 CCUGCCUC A GCCUCCUG 3462 CAGGAGGC CUGAUGAGGCCGUUAGGCCGAA IAGGCAGG 10112
2426 GCCUCAGC C UCCUGAGU 3463 ACUCAGGA CUGAUGAGGCCGUUAGGCCGAA ICUGAGGC 10113
2427 CCUCAGCC U CCUGAGUA 3464 UACUCAGG CUGAUGAGGCCGUUAGGCCGAA IGCUGAGG 10114
2429 UCAGCCUC C UGAGUAGC 3465 GCUACUCA CUGAUGAGGCCGUUAGGCCGAA IAGGCUGA 10115
2430 CAGCCUCC U GAGUAGCU 3466 AGCUACUC CUGAUGAGGCCGUUAGGCCGAA IGAGGCUG 10116
2438 UGAGUAGC U GGAUUACA 3467 UGUAAUCC CUGAUGAGGCCGUUAGGCCGAA ICUACUCA 10117
2446 UGGAUUAC A GGCAUGUG 3468 CACAUGCC CUGAUGAGGCCGUUAGGCCGAA IUAAUCCA 10118
2450 UUACAGGC A UGUGCCAC 3469 GUGGCACA CUGAUGAGGCCGUUAGGCCGAA ICCUGUAA 10119
2456 GCAUGUGC C ACCCACCC 3470 GGGUGGGU CUGAUGAGGCCGUUAGGCCGAA ICACAUGC 10120
2457 CAUGUGCC A CCCACCCA 3471 UGGGUGGG CUGAUGAGGCCGUUAGGCCGAA IGCACAUG 10121
2459 UGUGCCAC C CACCCAAC 3472 GUUGGGUG CUGAUGAGGCCGUUAGGCCGAA IUGGCACA 10122
2460 GUGCCACC C ACCCAACU 3473 AGUUGGGU CUGAUGAGGCCGUUAGGCCGAA IGUGGCAC 10123
2461 UGCCACCC A CCCAACUA 3474 UAGUUGGG CUGAUGAGGCCGUUAGGCCGAA IGGUGGCA 10124
2463 CCACCCAC C CAACUAAU 3475 AUUAGUUG CUGAUGAGGCCGUUAGGCCGAA IUGGGUGG 10125
2464 CACCCACC C AACUAAUU 3476 AAUUAGUU CUGAUGAGGCCGUUAGGCCGAA IGUGGGUG 10126
2465 ACCCACCC A ACUAAUUU 3477 AAAUUAGU CUGAUGAGGCCGUUAGGCCGAA IGGUGGGU 10127
2468 CACCCAAC U AAUUUUUG 3478 CAAAAAUU CUGAUGAGGCCGUUAGGCCGAA IUUGGGUG 10128
2493 AUAAAGAC A GGGUUUCA 3479 UGAAACCC CUGAUGAGGCCGUUAGGCCGAA IUCUUUAU 10129
2501 AGGGUUUC A CCAUGUUG 3480 CAACAUGG CUGAUGAGGCCGUUAGGCCGAA IAAACCCU 10130
2503 GGUUUCAC C AUGUUGGC 3481 GCCAACAU CUGAUGAGGCCGUUAGGCCGAA IUGAAACC 10131
2504 GUUUCACC A UGUUGGCC 3482 GGCCAACA CUGAUGAGGCCGUUAGGCCGAA IGUGAAAC 10132
2512 AUGUUGGC C AGGCUGGU 3483 ACCAGCCU CUGAUGAGGCCGUUAGGCCGAA ICCAACAU 10133
2513 UGUUGGCC A GGCUGGUC 3484 GACCAGCC CUGAUGAGGCCGUUAGGCCGAA IGCCAACA 10134
2517 GGCCAGGC U GGUCUCAA 3485 UUGAGACC CUGAUGAGGCCGUUAGGCCGAA ICCUGGCC 10135
2522 GGCUGGUC U CAAACUCC 3486 GGAGUUUG CUGAUGAGGCCGUUAGGCCGAA IACCAGCC 10136
2524 CUGGUCUC A AACUCCUG 3487 CAGGAGUU CUGAUGAGGCCGUUAGGCCGAA IAGACCAG 10137
2528 UCUCAAAC U CCUGACCU 3488 AGGUCAGG CUGAUGAGGCCGUUAGGCCGAA lUUUGAGA 10138
2530 UCAAACUC C UGACCUCA 3489 UGAGGUCA CUGAUGAGGCCGUUAGGCCGAA IAGUUUGA 10139
2531 CAAACUCC U GACCUCAA 3490 UUGAGGUC CUGAUGAGGCCGUUAGGCCGAA IGAGUUUG 10140
2535 CUCCUGAC C UCAAGUAA 3491 UUACUUGA CUGAUGAGGCCGUUAGGCCGAA IUCAGGAG 10141
2536 UCCUGACC U CAAGUAAU 3492 AUUACUUG CUGAUGAGGCCGUUAGGCCGAA IGUCAGGA 10142
2538 CUGACCUC A AGUAAUCC 3493 GGAUUACU CUGAUGAGGCCGUUAGGCCGAA IAGGUCAG 10143
2546 AAGUAAUC C ACCUGCCU 3494 AGGCAGGU CUGAUGAGGCCGUUAGGCCGAA IAUUACUU 10144
2547 AGUAAUCC A CCUGCCUC 3495 GAGGCAGG CUGAUGAGGCCGUUAGGCCGAA IGAUUACU 10145
2549 UAAUCCAC C UGCCUCGG 3496 CCGAGGCA CUGAUGAGGCCGUUAGGCCGAA IUGGAUUA 10146
2550 AAUCCACC U GCCUCGGC 3497 GCCGAGGC CUGAUGAGGCCGUUAGGCCGAA IGUGGAUU 10147
2553 CCACCUGC C UCGGCCUC 3498 GAGGCCGA CUGAUGAGGCCGUUAGGCCGAA ICAGGUGG 10148
2554 CACCUGCC U CGGCCUCC 3499 GGAGGCCG CUGAUGAGGCCGUUAGGCCGAA IGCAGGUG 10149
2559 GCCUCGGC C UCCCAAAG 3500 CUUUGGGA CUGAUGAGGCCGUUAGGCCGAA ICCGAGGC 10150
2560 CCUCGGCC U CCCAAAGU 3501 ACUUUGGG CUGAUGAGGCCGUUAGGCCGAA IGCCGAGG 10151
2562 UCGGCCUC C CAAAGUGC 3502 GCACUUUG CUGAUGAGGCCGUUAGGCCGAA IAGGCCGA 10152
2563 CGGCCUCC C AAAGUGCU 3503 AGCACUUU CUGAUGAGGCCGUUAGGCCGAA IGAGGCCG 10153
2564 GGCCUCCC A AAGUGCUG 3504 CAGCACUU CUGAUGAGGCCGUUAGGCCGAA IGGAGGCC 10154
2571 CAAAGUGC U GGGAUUAC 3505 GUAAUCCC CUGAUGAGGCCGUUAGGCCGAA ICACUUUG 10155 2580 GGGAUUAC A GGGAUGAG 3506 CUCAUCCC CUGAUGAGGCCGUUAGGCCGAA IUAAUCCC 10156
2590 GGAUGAGC C ACCGCGCC 3507 GGCGCGGU CUGAUGAGGCCGUUAGGCCGAA ICUCAUCC 10157
2591 GAUGAGCC A CCGCGCCC 3508 GGGCGCGG CUGAUGAGGCCGUUAGGCCGAA IGCUCAUC 10158
2593 UGAGCCAC C GCGCCCAG 3509 CUGGGCGC CUGAUGAGGCCGUUAGGCCGAA IUGGCUCA 10159
2598 CACCGCGC C CAGCCUCA 3510 UGAGGCUG CUGAUGAGGCCGUUAGGCCGAA ICGCGGUG 10160
2599 ACCGCGCC C AGCCUCAU 3511 AUGAGGCU CUGAUGAGGCCGUUAGGCCGAA IGCGCGGU 10161
2600 CCGCGCCC A GCCUCAUC 3512 GAUGAGGC CUGAUGAGGCCGUUAGGCCGAA IGGCGCGG 10162
2603 CGCCCAGC C UCAUCUCU 3513 AGAGAUGA CUGAUGAGGCCGUUAGGCCGAA ICUGGGCG 10163
2604 GCCCAGCC U CAUCUCUU 3514 AAGAGAUG CUGAUGAGGCCGUUAGGCCGAA IGCUGGGC 10164
2606 CCAGCCUC A UCUCUUUG 3515 CAAAGAGA CUGAUGAGGCCGUUAGGCCGAA IAGGCUGG 10165
2609 GCCUCAUC U CUUUGUUC 3516 GAACAAAG CUGAUGAGGCCGUUAGGCCGAA IAUGAGGC 10166
2611 CUCAUCUC U UUGUUCUA 3517 UAGAACAA CUGAUGAGGCCGUUAGGCCGAA IAGAUGAG 10167
2618 CUUUGUUC U AAAGAUGG 3518 CCAUCUUU CUGAUGAGGCCGUUAGGCCGAA IAACAAAG 10168
2633 GGAAAAAC C ACCCCCAA 3519 UUGGGGGU CUGAUGAGGCCGUUAGGCCGAA IUUUUUCC 10169
2634 GAAAAACC A CCCCCAAA 3520 UUUGGGGG CUGAUGAGGCCGUUAGGCCGAA IGUUUUUC 10170
2636 AAAACCAC C CCCAAAUU 3521 AAUUUGGG CUGAUGAGGCCGUUAGGCCGAA IUGGUUUU 10171
2637 AAACCACC C CCAAAUUU 3522 AAAUUUGG CUGAUGAGGCCGUUAGGCCGAA IGUGGUUU 10172
2638 AACCACCC C CAAAUUUU 3523 AAAAUUUG CUGAUGAGGCCGUUAGGCCGAA IGGUGGUU 10173
2639 ACCACCCC C AAAUUUUC 3524 GAAAAUUU CUGAUGAGGCCGUUAGGCCGAA IGGGUGGU 10174
2640 CCACCCCC A AAUUUUCU 3525 AGAAAAUU CUGAUGAGGCCGUUAGGCCGAA IGGGGUGG 10175
2648 AAAUUUUC U UUUUAUAC 3526 GUAUAAAA CUGAUGAGGCCGUUAGGCCGAA IAAAAUUU 10176
2657 UUUUAUAC U AUUAAUGA 3527 UCAUUAAU CUGAUGAGGCCGUUAGGCCGAA lUAUAAAA 10177
2669 AAUGAAUC A AUCAAUUC 3528 GAAUUGAU CUGAUGAGGCCGUUAGGCCGAA IAUUCAUU 10178
2673 AAUCAAUC A AUUCAUAU 3529 AUAUGAAU CUGAUGAGGCCGUUAGGCCGAA IAUUGAUU 10179
2678 AUCAAUUC A UAUCUAUU 3530 AAUAGAUA CUGAUGAGGCCGUUAGGCCGAA IAAUUGAU 10180
2683 UUCAUAUC U AUUUAUUA 3531 UAAUAAAU CUGAUGAGGCCGUUAGGCCGAA IAUAUGAA 10181
2698 UAAAUUUC U ACCGCUUU 3532 AAAGCGGU CUGAUGAGGCCGUUAGGCCGAA IAAAUUUA 10182
2701 AUUUCUAC C GCUUUUAG 3533 CUAAAAGC CUGAUGAGGCCGUUAGGCCGAA IUAGAAAU 10183
2704 UCUACCGC U UUUAGGCC 3534 GGCCUAAA CUGAUGAGGCCGUUAGGCCGAA ICGGUAGA 10184
2712 UUUUAGGC C AAAAAAAU 3535 AUUUUUUU CUGAUGAGGCCGUUAGGCCGAA ICCUAAAA 10185
2713 UUUAGGCC A AAAAAAUG 3536 CAUUUUUU CUGAUGAGGCCGUUAGGCCGAA IGCCUAAA 10186
2733 GAUCGUUC U CUGCCUCA 3537 UGAGGCAG CUGAUGAGGCCGUUAGGCCGAA IAACGAUC 10187
2735 UCGUUCUC U GCCUCACA 3538 UGUGAGGC CUGAUGAGGCCGUUAGGCCGAA IAGAACGA 10188
2738 UUCUCUGC C UCACAUAG 3539 CUAUGUGA CUGAUGAGGCCGUUAGGCCGAA ICAGAGAA 10189
2739 UCUCUGCC U CACAUAGC 3540 GCUAUGUG CUGAUGAGGCCGUUAGGCCGAA IGCAGAGA 10190
2741 UCUGCCUC A CAUAGCUU 3541 AAGCUAUG CUGAUGAGGCCGUUAGGCCGAA lAGGCAGA 10191
2743 UGCCUCAC A UAGCUUAC 3542 GUAAGCUA CUGAUGAGGCCGUUAGGCCGAA IUGAGGCA 10192
2748 CACAUAGC U UACAAGCC 3543 GGCUUGUA CUGAUGAGGCCGUUAGGCCGAA ICUAUGUG 10193
2752 UAGCUUAC A AGCCAGCU 3544 AGCUGGCU CUGAUGAGGCCGUUAGGCCGAA IUAAGCUA 10194
2756 UUACAAGC C AGCUGGAG 3545 CUCCAGCU CUGAUGAGGCCGUUAGGCCGAA ICUUGUAA 10195
2757 UACAAGCC A GCUGGAGA 3546 UCUCCAGC CUGAUGAGGCCGUUAGGCCGAA IGCUUGUA 10196
2760 AAGCCAGC U GGAGAAAU 3547 AUUUCUCC CUGAUGAGGCCGUUAGGCCGAA ICUGGCUU 10197
2776 UAUGGUAC U CAUUAAAA 3548 UUUUAAUG CUGAUGAGGCCGUUAGGCCGAA IUACCAUA 10198
2778 UGGUACUC A UUAAAAAA 3549 UUUUUUAA CUGAUGAGGCCGUUAGGCCGAA IAGUACCA 10199
Input Sequence = NM_002759. Cut Site = CH/ .
Arm Length = 8. Core Sequence = CUGAUGAG X CGAA (X = GCCGUUAGGC or other stem II)
NM_002759 (Homo sapiens protein kinase, interferon-inducible double stranded RNA dependent (PRKR), mRNA.; 2808 bp)
Underlined region can be any X sequence or linker, as described herein. "I" stands for Inosine.
Table XV: Human PKR Zinzyme and Substrate Sequence
Pos Substrate Seq ID Zinzyme Seq ID
10 CGGCGGCG G CGGCGCAG 3550 CUGCGCCG GCCGAAAGGCGAGUGAGGUCU CGCCGCCG 10200
13 CGGCGGCG G CGCAGUUU 3551 AAACUGCG GCCGAAAGGCGAGUGAGGUCU CGCCGCCG 10201
15 GCGGCGGC G CAGUUUGC 3552 GCAAACUG GCCGAAAGGCGAGUGAGGUCU GCCGCCGC 10202
18 GCGGCGCA G UUUGCUCA 3553 UGAGCAAA GCCGAAAGGCGAGUGAGGUCU UGCGCCGC 10203
22 CGCAGUUU G CUCAUACU 3554 AGUAUGAG GCCGAAAGGCGAGUGAGGUCU AAACUGCG 10204
33 CAUACUUU G UGACUUGC 3555 GCAAGUCA GCCGAAAGGCGAGUGAGGUCU AAAGUAUG 10205
40 UGUGACUU G CGGUCACA 3556 UGUGACCG GCCGAAAGGCGAGUGAGGUCU AAGUCACA 10206
43 GACUUGCG G UCACAGUG 3557 CACUGUGA GCCGAAAGGCGAGUGAGGUCU CGCAAGUC 10207
49 CGGUCACA G UGGCAUUC 3558 GAAUGCCA GCCGAAAGGCGAGUGAGGUCU UGUGACCG 10208
52 UCACAGUG G CAUUCAGC 3559 GCUGAAUG GCCGAAAGGCGAGUGAGGUCU CACUGUGA 10209
59 GGCAUUCA G CUCCACAC 3560 GUGUGGAG GCCGAAAGGCGAGUGAGGUCU UGAAUGCC 10210
71 CACACUUG G UAGAACCA 3561 UGGUUCUA GCCGAAAGGCGAGUGAGGUCU CAAGUGUG 10211
83 AACCACAG G CACGACAA 3562 UUGUCGUG GCCGAAAGGCGAGUGAGGUCU CUGUGGUU 10212
92 CACGACAA G CAUAGAAA 3563 UUUCUAUG GCCGAAAGGCGAGUGAGGUCU UUGUCGUG 10213
124 UCAUCGAG G CAUCGAGG 3564 CCUCGAUG GCCGAAAGGCGAGUGAGGUCU CUCGAUGA 10214
132 GCAUCGAG G UCCAUCCC 3565 GGGAUGGA GCCGAAAGGCGAGUGAGGUCU CUCGAUGC 10215
162 AGACCCUG G CUAUCAUA 3566 UAUGAUAG GCCGAAAGGCGAGUGAGGUCU CAGGGUCU 10216
178 AGACCUUA G UCUUCGCU 3567 AGCGAAGA GCCGAAAGGCGAGUGAGGUCU UAAGGUCU 10217
184 UAGUCUUC G CUGGUAUA 3568 UAUACCAG GCCGAAAGGCGAGUGAGGUCU GAAGACUA 10218
188 CUUCGCUG G UAUACUCG 3569 CGAGUAUA GCCGAAAGGCGAGUGAGGUCU CAGCGAAG 10219
196 GUAUACUC G CUGUCUGU 3570 ACAGACAG GCCGAAAGGCGAGUGAGGUCU GAGUAUAC 10220
199 UACUCGCU G UCUGUCAA 3571 UUGACAGA GCCGAAAGGCGAGUGAGGUCU AGCGAGUA 10221
203 CGCUGUCU G UCAACCAG 3572 CUGGUUGA GCCGAAAGGCGAGUGAGGUCU AGACAGCG 10222
211 GUCAACCA G CGGUUGAC 3573 GUCAACCG GCCGAAAGGCGAGUGAGGUCU UGGUUGAC 10223
214 AACCAGCG G UUGACUUU 3574 AAAGUCAA GCCGAAAGGCGAGUGAGGUCU CGCUGGUU 10224
229 UUUUUUAA G CCUUCUUU 3575 AAAGAAGG GCCGAAAGGCGAGUGAGGUCU UUAAAAAA 10225
252 UUUUACCA G UUUCUGGA 3576 UCCAGAAA GCCGAAAGGCGAGUGAGGUCU UGGUAAAA 10226
261 UUUCUGGA G CAAAUUCA 3577 UGAAUUUG GCCGAAAGGCGAGUGAGGUCU UCCAGAAA 10227
270 CAAAUUCA G UUUGCCUU 3578 AAGGCAAA GCCGAAAGGCGAGUGAGGUCU UGAAUUUG 10228
274 UUCAGUUU G CCUUCCUG 3579 CAGGAAGG GCCGAAAGGCGAGUGAGGUCU AAACUGAA 10229
288 CUGGAUUU G UAAAUUGU 3580 ACAAUUUA GCCGAAAGGCGAGUGAGGUCU AAAUCCAG 10230
295 UGUAAAUU G UAAUGACC 3581 GGUCAUUA GCCGAAAGGCGAGUGAGGUCU AAUUUACA 10231
315 AAACUUUA G CAGUUCUU 3582 AAGAACUG GCCGAAAGGCGAGUGAGGUCU UAAAGUUU 10232
318 CUUUAGCA G UUCUUCCA 3583 UGGAAGAA GCCGAAAGGCGAGUGAGGUCU UGCUAAAG 10233
337 UGACUCAG G UUUGCUUC 3584 GAAGCAAA GCCGAAAGGCGAGUGAGGUCU CUGAGUCA 10234
341 UCAGGUUU G CUUCUCUG 3585 CAGAGAAG GCCGAAAGGCGAGUGAGGUCU AAACCUGA 10235
350 CUUCUCUG G CGGUCUUC 3586 GAAGACCG GCCGAAAGGCGAGUGAGGUCU CAGAGAAG 10236
353 CUCUGGCG G UCUUCAGA 3587 UCUGAAGA GCCGAAAGGCGAGUGAGGUCU CGCCAGAG 10237
380 ACACUUCC G UGAUUAUC 3588 GAUAAUCA GCCGAAAGGCGAGUGAGGUCU GGAAGUGU 10238
390 GAUUAUCU G CGUGCAUU 3589 AAUGCACG GCCGAAAGGCGAGUGAGGUCU AGAUAAUC 10239
392 UUAUCUGC G UGCAUUUU 3590 AAAAUGCA GCCGAAAGGCGAGUGAGGUCU GCAGAUAA 10240
394 AUCUGCGU G CAUUUUGG 3591 CCAAAAUG GCCGAAAGGCGAGUGAGGUCU ACGCAGAU 10241
408 UGGACAAA G CUUCCAAC 3592 GUUGGAAG GCCGAAAGGCGAGUGAGGUCU UUUGUCCA 10242
439 AAGAAAUG G CUGGUGAU 3593 AUCACCAG GCCGAAAGGCGAGUGAGGUCU CAUUUCUU 10243
443 AAUGGCUG G UGAUCUUU 3594 AAAGAUCA GCCGAAAGGCGAGUGAGGUCU CAGCCAUU 10244
454 AUCUUUCA G CAGGUUUC 3595 GAAACCUG GCCGAAAGGCGAGUGAGGUCU UGAAAGAU 10245
458 UUCAGCAG G UUUCUUCA 3596 UGAAGAAA GCCGAAAGGCGAGUGAGGUCU CUGCUGAA 10246 488 UACAUACC G UCAGAAGC 3597 GCUUCUGA GCCGAAAGGCGAGUGAGGUCU GGUAUGUA 10247
495 CGUCAGAA G CAGGGAGU 3598 ACUCCCUG GCCGAAAGGCGAGUGAGGUCU UUCUGACG 10248
502 AGCAGGGA G UAGUACUU 3599 AAGUACUA GCCGAAAGGCGAGUGAGGUCU UCCCUGCU 10249
505 AGGGAGUA G UACUUAAA 3600 UUUAAGUA GCCGAAAGGCGAGUGAGGUCU UACUCCCU 10250
525 CAAGAACU G CCUAAUUC 3601 GAAUUAGG GCCGAAAGGCGAGUGAGGUCU AGUUCUUG 10251
555 GAUAGGAG G UUUACAUU 3602 AAUGUAAA GCCGAAAGGCGAGUGAGGUCU CUCCUAUC 10252
568 CAUUUCAA G UUAUAAUA 3603 UAUUAUAA GCCGAAAGGCGAGUGAGGUCU UUGAAAUG 10253
599 UCCAGAAG G UGAAGGUA 3604 UACCUUCA GCCGAAAGGCGAGUGAGGUCU CUUCUGGA 10254
605 AGGUGAAG G UAGAUCAA 3605 UUGAUCUA GCCGAAAGGCGAGUGAGGUCU CUUCACCU 10255
622 AGAAGGAA G CAAAAAAU 3606 AUUUUUUG GCCGAAAGGCGAGUGAGGUCU UCCUUCU 10256
631 CAAAAAAU G CCGCAGCC 3607 GGCUGCGG GCCGAAAGGCGAGUGAGGUCU AUUUUUUG 10257
634 AAAAUGCC G CAGCCAAA 3608 UUUGGCUG GCCGAAAGGCGAGUGAGGUCU GGCAUUUU 10258
637 AUGCCGCA G CCAAAUUA 3609 UAAUUUGG GCCGAAAGGCGAGUGAGGUCU UGCGGCAU 10259
646 CCAAAUUA G CUGUUGAG 3610 CUCAACAG GCCGAAAGGCGAGUGAGGUCU UAAUUUGG 10260
649 AAUUAGCU G UUGAGAUA 3611 UAUCUCAA GCCGAAAGGCGAGUGAGGUCU AGCUAAUU 10261
676 AAAAGAAG G CAGUUAGU 3612 ACUAACUG GCCGAAAGGCGAGUGAGGUCU CUUCUUUU 10262
679 AGAAGGCA G UUAGUCCU 3613 AGGACUAA GCCGAAAGGCGAGUGAGGUCU UGCCUUCU 10263
683 GGCAGUUA G UCCUUUAU 3614 AUAAAGGA GCCGAAAGGCGAGUGAGGUCU UAACUGCC 10264
743 UUACAUAG G CCUUAUCA 3615 UGAUAAGG GCCGAAAGGCGAGUGAGGUCU CUAUGUAA 10265
760 AUAGAAUU G CCCAGAAG 3616 CUUCUGGG GCCGAAAGGCGAGUGAGGUCU AAUUCUAU 10266
781 GACUAACU G UAAAUUAU 3617 AUAAUUUA GCCGAAAGGCGAGUGAGGUCU AGUUAGUC 10267
795 UAUGAACA G UGUGCAUC 3618 GAUGCACA GCCGAAAGGCGAGUGAGGUCU UGUUCAUA 10268
797 UGAACAGU G UGCAUCGG 3619 CCGAUGCA GCCGAAAGGCGAGUGAGGUCU ACUGUUCA 10269
799 AACAGUGU G CAUCGGGG 3620 CCCCGAUG GCCGAAAGGCGAGUGAGGUCU ACACUGUU 10270
808 CAUCGGGG G UGCAUGGG 3621 CCCAUGCA GCCGAAAGGCGAGUGAGGUCU CCCCGAUG 10271
810 UCGGGGGU G CAUGGGCC 3622 GGCCCAUG GCCGAAAGGCGAGUGAGGUCU ACCCCCGA 10272
816 GUGCAUGG G CCAGAAGG 3623 CCUUCUGG GCCGAAAGGCGAGUGAGGUCU CCAUGCAC 10273
839 UUAUAAAU G CAAAAUGG 3624 CCAUUUUG GCCGAAAGGCGAGUGAGGUCU AUUUAUAA 10274
863 AGAAUAUA G UAUUGGUA 3625 UACCAAUA GCCGAAAGGCGAGUGAGGUCU UAUAUUCU 10275
869 UAGUAUUG G UACAGGUU 3626 AACCUGUA GCCGAAAGGCGAGUGAGGUCU CAAUACUA 10276
875 UGGUACAG G UUCUACUA 3627 UAGUAGAA GCCGAAAGGCGAGUGAGGUCU CUGUACCA 10277
892 AACAGGAA G CAAAACAA 3628 UUGUUUUG GCCGAAAGGCGAGUGAGGUCU UUCCUGUU 10278
904 AACAAUUG G CCGCUAAA 3629 UUUAGCGG GCCGAAAGGCGAGUGAGGUCU CAAUUGUU 10279
907 AAUUGGCC G CUAAACUU 3630 AAGUUUAG GCCGAAAGGCGAGUGAGGUCU GGCCAAUU 10280
916 CUAAACUU G CAUAUCUU 3631 AAGAUAUG GCCGAAAGGCGAGUGAGGUCU AAGUUUAG 10281
949 AAACCUCA G UGAAAUCU 3632 AGAUUUCA GCCGAAAGGCGAGUGAGGUCU UGAGGUUU 10282
966 GACUACCU G UCCUCUGG 3633 CCAGAGGA GCCGAAAGGCGAGUGAGGUCU AGGUAGUC 10283
974 GUCCUCUG G UUCUUUUG 3634 CAAAAGAA GCCGAAAGGCGAGUGAGGUCU CAGAGGAC 10284
982 GUUCUUUU G CUACUACG 3635 CGUAGUAG GCCGAAAGGCGAGUGAGGUCU AAAAGAAC 10285
990 GCUACUAC G UGUGAGUC 3636 GACUCACA GCCGAAAGGCGAGUGAGGUCU GUAGUAGC 10286
992 UACUACGU G UGAGUCCC 3637 GGGACUCA GCCGAAAGGCGAGUGAGGUCU ACGUAGUA 10287
996 ACGUGUGA G UCCCAAAG 3638 CUUUGGGA GCCGAAAGGCGAGUGAGGUCU UCACACGU 10288
1004 GUCCCAAA G CAACUCUU 3639 AAGAGUUG GCCGAAAGGCGAGUGAGGUCU UUUGGGAC 10289
1015 ACUCUUUA G UGACCAGC 3640 GCUGGUCA GCCGAAAGGCGAGUGAGGUCU UAAAGAGU 10290
1022 AGUGACCA G CACACUCG 3641 CGAGUGUG GCCGAAAGGCGAGUGAGGUCU UGGUCACU 10291
1030 GCACACUC G CUUCUGAA 3642 UUCAGAAG GCCGAAAGGCGAGUGAGGUCU GAGUGUGC 10292
1052 AUCUGAAG G UGACUUCU 3643 AGAAGUCA GCCGAAAGGCGAGUGAGGUCU CUUCAGAU 10293
1063 ACUUCUCA G CAGAUACA 3644 UGUAUCUG GCCGAAAGGCGAGUGAGGUCU UGAGAAGU 10294
1091 UUCUAACA G UGACAGUU 3645 AACUGUCA GCCGAAAGGCGAGUGAGGUCU UGUUAGAA 10295
1097 CAGUGACA G UUUAAACA 3646 UGUUUAAA GCCGAAAGGCGAGUGAGGUCU UGUCACUG 10296
1106 UUUAAACA G UUCUUCGU 3647 ACGAAGAA GCCGAAAGGCGAGUGAGGUCU UGUUUAAA 10297 1113 AGUUCUUC G UUGCUUAU 3648 AUAAGCAA GCCGAAAGGCGAGUGAGGUCU GAAGAACU 10298
1116 UCUUCGUU G CUUAUGAA 3649 UUCAUAAG GCCGAAAGGCGAGUGAGGUCU AACGAAGA 10299
1127 UAUGAAUG G UCUCAGAA 3650 UUCUGAGA GCCGAAAGGCGAGUGAGGUCU CAUUCAUA 10300
1150 AAAGGAAG G CAAAAAGA 3651 UCUUUUUG GCCGAAAGGCGAGUGAGGUCU CUUCCUUU 10301
1165 GAUCUUUG G CACCCAGA 3652 UCUGGGUG GCCGAAAGGCGAGUGAGGUCU CAAAGAUC 10302
1203 GAAACAAA G UAUACUGU 3653 ACAGUAUA GCCGAAAGGCGAGUGAGGUCU UUUGUUUC 10303
1210 AGUAUACU G UGGACAAG 3654 CUUGUCCA GCCGAAAGGCGAGUGAGGUCU AGUAUACU 10304
1221 GAGAAGAG G UUUGGCAU 3655 AUGCCAAA GCCGAAAGGCGAGUGAGGUCU CUCUUGUC 10305
1226 GAGGUUUG G CAUGGAUU 3656 AAUCCAUG GCCGAAAGGCGAGUGAGGUCU CAAACCUC 10306
1256 AUUAAUUG G CUCAGGUG 3657 CACCUGAG GCCGAAAGGCGAGUGAGGUCU CAAUUAAU 10307
1262 UGGCUCAG G UGGAUUUG 3658 CAAAUCCA GCCGAAAGGCGAGUGAGGUCU CUGAGCCA 10308
1271 UGGAUUUG G CCAAGUUU 3659 AAACUUGG GCCGAAAGGCGAGUGAGGUCU CAAAUCCA 10309
1276 UUGGCCAA G UUUUCAAA 3660 UUUGAAAA GCCGAAAGGCGAGUGAGGUCU UUGGCCAA 10310
1285 UUUUCAAA G CAAAACAC 3661 GUGUUUUG GCCGAAAGGCGAGUGAGGUCU UUUGAAAA 10311
1315 AGACUUAC G UUAUUAAA 3662 UUUAAUAA GCCGAAAGGCGAGUGAGGUCU GUAAGUCU 10312
1325 UAUUAAAC G UGUUAAAU 3663 AUUUAACA GCCGAAAGGCGAGUGAGGUCU GUUUAAUA 10313
1327 UUAAACGU G UUAAAUAU 3664 AUAUUUAA GCCGAAAGGCGAGUGAGGUCU ACGUUUAA 10314
1348 ACGAGAAG G CGGAGCGU 3665 ACGCUCCG GCCGAAAGGCGAGUGAGGUCU CUUCUCGU 10315
1353 AAGGCGGA G CGUGAAGU 3666 ACUUCACG GCCGAAAGGCGAGUGAGGUCU UCCGCCUU 10316
1355 GGCGGAGC G UGAAGUAA 3667 UUACUUCA GCCGAAAGGCGAGUGAGGUCU GCUCCGCC 10317
1360 AGCGUGAA G UAAAAGCA 3668 UGCUUUUA GCCGAAAGGCGAGUGAGGUCU UUCACGCU 10318
1366 AAGUAAAA G CAUUGGCA 3669 UGCCAAUG GCCGAAAGGCGAGUGAGGUCU UUUUACUU 10319
1372 AAGCAUUG G CAAAACUU 3670 AAGUUUUG GCCGAAAGGCGAGUGAGGUCU CAAUGCUU 10320
1387 UUGAUCAU G UAAAUAUU 3671 AAUAUUUA GCCGAAAGGCGAGUGAGGUCU AUGAUCAA 10321
1396 UAAAUAUU G UUCACUAC 3672 GUAGUGAA GCCGAAAGGCGAGUGAGGUCU AAUAUUUA 10322
1409 CUACAAUG G CUGUUGGG 3673 CCCAACAG GCCGAAAGGCGAGUGAGGUCU CAUUGUAG 10323
1412 CAAUGGCU G UUGGGAUG 3674 CAUCCCAA GCCGAAAGGCGAGUGAGGUCU AGCCAUUG 10324
1445 UGAGACCA G UGAUGAUU 3675 AAUCAUCA GCCGAAAGGCGAGUGAGGUCU UGGUCUCA 10325
1463 UCUUGAGA G CAGUGAUU 3676 AAUCACUG GCCGAAAGGCGAGUGAGGUCU UCUCAAGA 10326
1466 UGAGAGCA G UGAUUAUG 3677 CAUAAUCA GCCGAAAGGCGAGUGAGGUCU UGCUCUCA 10327
1487 UGAGAACA G CAAAAAUA 3678 UAUUUUUG GCCGAAAGGCGAGUGAGGUCU UGUUCUCA 10328
1496 CAAAAAUA G UUCAAGGU 3679 ACCUUGAA GCCGAAAGGCGAGUGAGGUCU UAUUUUUG 10329
1503 AGUUCAAG G UCAAAGAC 3680 GUCUUUGA GCCGAAAGGCGAGUGAGGUCU CUUGAACU 10330
1515 AAGACUAA G UGCCUUUU 3681 AAAAGGCA GCCGAAAGGCGAGUGAGGUCU UUAGUCUU 10331
1517 GACUAAGU G CCUUUUCA 3682 UGAAAAGG GCCGAAAGGCGAGUGAGGUCU ACUUAGUC 10332
1541 GGAAUUCU G UGAUAAAG 3683 CUUUAUCA GCCGAAAGGCGAGUGAGGUCU AGAAUUCC 10333
1583 AAGAAGAG G CGAGAAAC 3684 GUUUCUCG GCCGAAAGGCGAGUGAGGUCU CUCUUCUU 10334
1600 UAGACAAA G UUUUGGCU 3685 AGCCAAAA GCCGAAAGGCGAGUGAGGUCU UUUGUCUA 10335
1606 AAGUUUUG G CUUUGGAA 3686 UUCCAAAG GCCGAAAGGCGAGUGAGGUCU CAAAACUU 10336
1639 CAAAAGGG G UGGAUUAU 3687 AUAAUCCA GCCGAAAGGCGAGUGAGGUCU CCCUUUUG 10337
1683 GAUCUUAA G CCAAGUAA 3688 UUACUUGG GCCGAAAGGCGAGUGAGGUCU UUAAGAUC 10338
1688 UAAGCCAA G UAAUAUAU 3689 AUAUAUUA GCCGAAAGGCGAGUGAGGUCU UUGGCUUA 10339
1702 UAUUCUUA G UAGAUACA 3690 UGUAUCUA GCCGAAAGGCGAGUGAGGUCU UAAGAAUA 10340
1717 CAAAACAA G UAAAGAUU 3691 AAUCUUUA GCCGAAAGGCGAGUGAGGUCU UUGUUUUG 10341
1741 UUGGACUU G UAACAUCU 3692 AGAUGUUA GCCGAAAGGCGAGUGAGGUCU AAGUCCAA 10342
1767 GAUGGAAA G CGAACAAG 3693 CUUGUUCG GCCGAAAGGCGAGUGAGGUCU UUUCCAUC 10343
1778 AAGAAGGA G UAAGGGAA 3694 UUCCCUUA GCCGAAAGGCGAGUGAGGUCU UCCUUGUU 10344
1791 GGAACUUU G CGAUACAU 3695 AUGUAUCG GCCGAAAGGCGAGUGAGGUCU AAAGUUCC 10345
1802 AUACAUGA G CCCAGAAC 3696 GUUCUGGG GCCGAAAGGCGAGUGAGGUCU UCAUGUAU 10346
1821 AUUUCUUC G CAAGACUA 3697 UAGUCUUG GCCGAAAGGCGAGUGAGGUCU GAAGAAAU 10347
1840 GAAAGGAA G UGGACCUC 3698 GAGGUCCA GCCGAAAGGCGAGUGAGGUCU UUCCUUUC 10348 1852 ACCUCUAC G CUUUGGGG 3699 CCCCAAAG GCCGAAAGGCGAGUGAGGUCU GUAGAGGU 10349
1860 GCUUUGGG G CUAAUUCU 3700 AGAAUUAG GCCGAAAGGCGAGUGAGGUCU CCCAAAGC 10350
1870 UAAUUCUU G CUGAACUU 3701 AAGUUCAG GCCGAAAGGCGAGUGAGGUCU AAGAAUUA 10351
1885 UUCUUCAU G UAUGUGAC 3702 GUCACAUA GCCGAAAGGCGAGUGAGGUCU AUGAAGAA 10352
1889 UCAUGUAU G UGACACUG 3703 CAGUGUCA GCCGAAAGGCGAGUGAGGUCU AUACAUGA 10353
1897 GUGACACU G CUUUUGAA 3704 UUCAAAAG GCCGAAAGGCGAGUGAGGUCU AGUGUCAC 10354
1914 ACAUCAAA G UUUUUCAC 3705 GUGAAAAA GCCGAAAGGCGAGUGAGGUCU UUUGAUGU 10355
1937 ACGGGAUG G CAUCAUCU 3706 AGAUGAUG GCCGAAAGGCGAGUGAGGUCU CAUCCCGU 10356
2047 CCUUGACU G UGUGGAAG 3707 CUUCCACA GCCGAAAGGCGAGUGAGGUCU AGUCAAGG 10357
2049 UUGACUGU G UGGAAGAA 3708 UUCUUCCA GCCGAAAGGCGAGUGAGGUCU ACAGUCAA 10358
2060 GAAGAAAA G CCCAGAGA 3709 UCUCUGGG GCCGAAAGGCGAGUGAGGUCU UUUUCUUC 10359
2087 ACACACAU G UUAGAGCC 3710 GGCUCUAA GCCGAAAGGCGAGUGAGGUCU AUGUGUGU 10360
2093 AUGUUAGA G CCCUUCUG 3711 CAGAAGGG GCCGAAAGGCGAGUGAGGUCU UCUAACAU 10361
2107 CUGAAAAA G UAUCCUGC 3712 GCAGGAUA GCCGAAAGGCGAGUGAGGUCU UUUUUCAG 10362
2114 AGUAUCCU G CUUCUGAU 3713 AUCAGAAG GCCGAAAGGCGAGUGAGGUCU AGGAUACU 10363
2125 UCUGAUAU G CAGUUUUC 3714 GAAAACUG GCCGAAAGGCGAGUGAGGUCU AUAUCAGA 10364
2128 GAUAUGCA G UUUUCCUU 3715 AAGGAAAA GCCGAAAGGCGAGUGAGGUCU UGCAUAUC 10365
2153 UAAAAUCU G CUAGGGAA 3716 UUCCCUAG GCCGAAAGGCGAGUGAGGUCU AGAUUUUA 10366
2192 AUUUUAAU G UUUCCUUU 3717 AAAGGAAA GCCGAAAGGCGAGUGAGGUCU AUUAAAAU 10367
2230 AUCUUUCU G CAGAAACA 3718 UGUUUCUG GCCGAAAGGCGAGUGAGGUCU AGAAAGAU 10368
2244 ACAGAAAG G UUUUCUUC 3719 GAAGAAAA GCCGAAAGGCGAGUGAGGUCU CUUUCUGU 10369
2258 UUCUUUUU G CUUCAAAA 3720 UUUUGAAG GCCGAAAGGCGAGUGAGGUCU AAAAAGAA 10370
2293 UUUUCCUG G CUCAUCUC 3721 GAGAUGAG GCCGAAAGGCGAGUGAGGUCU CAGGAAAA 10371
2332 AAGACAGA G UCUCGCUC 3722 GAGCGAGA GCCGAAAGGCGAGUGAGGUCU UCUGUCUU 10372
2337 AGAGUCUC G CUCUGUUG 3723 CAACAGAG GCCGAAAGGCGAGUGAGGUCU GAGACUCU 10373
2342 CUCGCUCU G UUGCCCAG 3724 CUGGGCAA GCCGAAAGGCGAGUGAGGUCU AGAGCGAG 10374
2345 GCUCUGUU G CCCAGGCU 3725 AGCCUGGG GCCGAAAGGCGAGUGAGGUCU AACAGAGC 10375
2351 UUGCCCAG G CUGGAGUG 3726 CACUCCAG GCCGAAAGGCGAGUGAGGUCU CUGGGCAA 10376
2357 AGGCUGGA G UGCAAUGA 3727 UCAUUGCA GCCGAAAGGCGAGUGAGGUCU UCCAGCCU 10377
2359 GCUGGAGU G CAAUGACA 3728 UGUCAUUG GCCGAAAGGCGAGUGAGGUCU ACUCCAGC 10378
2370 AUGACACA G UCUUGGCU 3729 AGCCAAGA GCCGAAAGGCGAGUGAGGUCU UGUGUCAU 10379
2376 CAGUCUUG G CUCACUGC 3730 GCAGUGAG GCCGAAAGGCGAGUGAGGUCU CAAGACUG 10380
2383 GGCUCACU G CAACUUCU 3731 AGAAGUUG GCCGAAAGGCGAGUGAGGUCU AGUGAGCC 10381
2392 CAACUUCU G CCUCUUGG 3732 CCAAGAGG GCCGAAAGGCGAGUGAGGUCU AGAAGUUG 10382
2401 CCUCUUGG G UUCAAGUG 3733 CACUUGAA GCCGAAAGGCGAGUGAGGUCU CCAAGAGG 10383
2407 GGGUUCAA G UGAUUCUC 3734 GAGAAUCA GCCGAAAGGCGAGUGAGGUCU UUGAACCC 10384
2418 AUUCUCCU G CCUCAGCC 3735 GGCUGAGG GCCGAAAGGCGAGUGAGGUCU AGGAGAAU 10385
2424 CUGCCUCA G CCUCCUGA 3736 UCAGGAGG GCCGAAAGGCGAGUGAGGUCU UGAGGCAG 10386
2433 CCUCCUGA G UAGCUGGA 3737 UCCAGCUA GCCGAAAGGCGAGUGAGGUCU UCAGGAGG 10387
2436 CCUGAGUA G CUGGAUUA 3738 UAAUCCAG GCCGAAAGGCGAGUGAGGUCU UACUCAGG 10388
2448 GAUUACAG G CAUGUGCC 3739 GGCACAUG GCCGAAAGGCGAGUGAGGUCU CUGUAAUC 10389
2452 ACAGGCAU G UGCCACCC 3740 GGGUGGCA GCCGAAAGGCGAGUGAGGUCU AUGCCUGU 10390
2454 AGGCAUGU G CCACCCAC 3741 GUGGGUGG GCCGAAAGGCGAGUGAGGUCU ACAUGCCU 10391
2476 UAAUUUUU G UGUUUUUA 3742 UAAAAACA GCCGAAAGGCGAGUGAGGUCU AAAAAUUA 10392
2478 AUUUUUGU G UUUUUAAU 3743 AUUAAAAA GCCGAAAGGCGAGUGAGGUCU ACAAAAAU 10393
2496 AAGACAGG G UUUCACCA 3744 UGGUGAAA GCCGAAAGGCGAGUGAGGUCU CCUGUCUU 10394
2506 UUCACCAU G UUGGCCAG 3745 CUGGCCAA GCCGAAAGGCGAGUGAGGUCU AUGGUGAA 10395
2510 CCAUGUUG G CCAGGCUG 3746 CAGCCUGG GCCGAAAGGCGAGUGAGGUCU CAACAUGG 10396
2515 UUGGCCAG G CUGGUCUC 3747 GAGACCAG GCCGAAAGGCGAGUGAGGUCU CUGGCCAA 10397
2519 CCAGGCUG G UCUCAAAC 3748 GUUUGAGA GCCGAAAGGCGAGUGAGGUCU CAGCCUGG 10398
2540 GACCUCAA G UAAUCCAC 3749 GUGGAUUA GCCGAAAGGCGAGUGAGGUCU UUGAGGUC 10399 2551 AUCCACCU G CCUCGGCC 3750 GGCCGAGG GCCGAAAGGCGAGUGAGGUCU AGGUGGAU 10400
2557 CUGCCUCG G CCUCCCAA 3751 UUGGGAGG GCCGAAAGGCGAGUGAGGUCU CGAGGCAG 10401
2567 CUCCCAAA G UGCUGGGA 3752 UCCCAGCA GCCGAAAGGCGAGUGAGGUCU UUUGGGAG 10402
2569 CCCAAAGU G CUGGGAUU 3753 AAUCCCAG GCCGAAAGGCGAGUGAGGUCU ACUUUGGG 10403
2588 AGGGAUGA G CCACCGCG 3754 CGCGGUGG GCCGAAAGGCGAGUGAGGUCU UCAUCCCU 10404
2594 GAGCCACC G CGCCCAGC 3755 GCUGGGCG GCCGAAAGGCGAGUGAGGUCU GGUGGCUC 10405
2596 GCCACCGC G CCCAGCCU 3756 AGGCUGGG GCCGAAAGGCGAGUGAGGUCU GCGGUGGC 10406
2601 CGCGCCCA G CCUCAUCU 3757 AGAUGAGG GCCGAAAGGCGAGUGAGGUCU UGGGCGCG 10407
2614 AUCUCUUU G UUCUAAAG 3758 CUUUAGAA GCCGAAAGGCGAGUGAGGUCU AAAGAGAU 10408
2702 UUUCUACC G CUUUUAGG 3759 CCUAAAAG GCCGAAAGGCGAGUGAGGUCU GGUAGAAA 10409
2710 GCUUUUAG G CCAAAAAA 3760 UUUUUUGG GCCGAAAGGCGAGUGAGGUCU CUAAAAGC 10410
2721 AAAAAAAU G UAAGAUCG 3761 CGAUCUUA GCCGAAAGGCGAGUGAGGUCU AUUUUUUU 10411
2729 GUAAGAUC G UUCUCUGC 3762 GCAGAGAA GCCGAAAGGCGAGUGAGGUCU GAUCUUAC 10412
2736 CGUUCUCU G CCUCACAU 3763 AUGUGAGG GCCGAAAGGCGAGUGAGGUCU AGAGAACG 10413
2746 CUCACAUA G CUUACAAG 3764 CUUGUAAG GCCGAAAGGCGAGUGAGGUCU UAUGUGAG 10414
2754 GCUUACAA G CCAGCUGG 3765 CCAGCUGG GCCGAAAGGCGAGUGAGGUCU UUGUAAGC 10415
2758 ACAAGCCA G CUGGAGAA 3766 UUCUCCAG GCCGAAAGGCGAGUGAGGUCU UGGCUUGU 10416
2772 GAAAUAUG G UACUCAUU 3767 AAUGAGUA GCCGAAAGGCGAGUGAGGUCU CAUAUUUC 10417
2796 AAAAAAAA G UGAUGUAC 3768 GUACAUCA GCCGAAAGGCGAGUGAGGUCU UUUUUUUU 10418
Input Sequence = NM_002759. Cut Site = G/Y
Arm Length = 8. Core Sequence = GCcgaaagGCGaGuCaaGGuCu
NM_002759 (Homo sapiens protein kinase, interferon-inducible double stranded RNA dependent (PRKR), mRNA.; 2808 bp)
Table XVI: Human PKR DNAzyme and Substrate Sequence
Pos Substrate Seq ID DNAzyme Seq ID
10 CGGCGGCG G CGGCGCAG 3550 CTGCGCCG GGCTAGCTACAACGA CGCCGCCG 10419
13 CGGCGGCG G CGCAGUUU 3551 AAACTGCG GGCTAGCTACAACGA CGCCGCCG 10420
15 GCGGCGGC G CAGUUUGC 3552 GCAAACTG GGCTAGCTACAACGA GCCGCCGC 10421
18 GCGGCGCA G UUUGCUCA 3553 TGAGCAAA GGCTAGCTACAACGA TGCGCCGC 10422
22 CGCAGUUU G CUCAUACU 3554 AGTATGAG GGCTAGCTACAACGA AAACTGCG 10423
26 GUUUGCUC A UACUUUGU 3053 ACAAAGTA GGCTAGCTACAACGA GAGCAAAC 10424
28 UUGCUCAU A CUUUGUGA 2423 TCACAAAG GGCTAGCTACAACGA ATGAGCAA 10425
33 CAUACUUU G UGACUUGC 3555 GCAAGTCA GGCTAGCTACAACGA AAAGTATG 10426
36 ACUUUGUG A CUUGCGGU 3769 ACCGCAAG GGCTAGCTACAACGA CACAAAGT 10427
40 UGUGACUU G CGGUCACA 3556 TGTGACCG GGCTAGCTACAACGA AAGTCACA 10428
43 GACUUGCG G UCACAGUG 3557 CACTGTGA GGCTAGCTACAACGA CGCAAGTC 10429
46 UUGCGGUC A CAGUGGCA 3056 TGCCACTG GGCTAGCTACAACGA GACCGCAA 10430
49 CGGUCACA G UGGCAUUC 3558 GAATGCCA GGCTAGCTACAACGA TGTGACCG 10431
52 UCACAGUG G CAUUCAGC 3559 GCTGAATG GGCTAGCTACAACGA CACTGTGA 10432
54 ACAGUGGC A UUCAGCUC 3058 GAGCTGAA GGCTAGCTACAACGA GCCACTGT 10433
59 GGCAUUCA G CUCCACAC 3560 GTGTGGAG GGCTAGCTACAACGA TGAATGCC 10434
64 UCAGCUCC A CACUUGGU 3062 ACCAAGTG GGCTAGCTACAACGA GGAGCTGA 10435
66 AGCUCCAC A CUUGGUAG 3063 CTACCAAG GGCTAGCTACAACGA GTGGAGCT 10436
71 CACACUUG G UAGAACCA 3561 TGGTTCTA GGCTAGCTACAACGA CAAGTGTG 10437
76 UUGGUAGA A CCACAGGC 3770 GCCTGTGG GGCTAGCTACAACGA TCTACCAA 10438
79 GUAGAACC A CAGGCACG 3066 CGTGCCTG GGCTAGCTACAACGA GGTTCTAC 10439
83 AACCACAG G CACGACAA 3562 TTGTCGTG GGCTAGCTACAACGA CTGTGGTT 10440
85 CCACAGGC A CGACAAGC 3068 GCTTGTCG GGCTAGCTACAACGA GCCTGTGG 10441
88 CAGGCACG A CAAGCAUA 3771 TATGCTTG GGCTAGCTACAACGA CGTGCCTG 10442
92 CACGACAA G CAUAGAAA 3563 TTTCTATG GGCTAGCTACAACGA TTGTCGTG 10443
94 CGACAAGC A UAGAAACA 3070 TGTTTCTA GGCTAGCTACAACGA GCTTGTCG 10444
100 GCAUAGAA A CAUCCUAA 3772 TTAGGATG GGCTAGCTACAACGA TTCTATGC 10445
102 AUAGAAAC A UCCUAAAC 3071 GTTTAGGA GGCTAGCTACAACGA GTTTCTAT 10446
109 CAUCCUAA A CAAUCUUC 3773 GAAGATTG GGCTAGCTACAACGA TTAGGATG 10447
112 CCUAAACA A UCUUCAUC 3774 GATGAAGA GGCTAGCTACAACGA TGTTTAGG 10448
118 CAAUCUUC A UCGAGGCA 3076 TGCCTCGA GGCTAGCTACAACGA GAAGATTG 10449
124 UCAUCGAG G CAUCGAGG 3564 CCTCGATG GGCTAGCTACAACGA CTCGATGA 10450
126 AUCGAGGC A UCGAGGUC 3077 GACCTCGA GGCTAGCTACAACGA GCCTCGAT 10451
132 GCAUCGAG G UCCAUCCC 3565 GGGATGGA GGCTAGCTACAACGA CTCGATGC 10452
136 CGAGGUCC A UCCCAAUA 3079 TATTGGGA GGCTAGCTACAACGA GGACCTCG 10453
142 CCAUCCCA A UAAAAAUC 3775 GATTTTTA GGCTAGCTACAACGA TGGGATGG 10454
148 CAAUAAAA A UCAGGAGA 3776 TCTCCTGA GGCTAGCTACAACGA TTTTATTG 10455
156 AUCAGGAG A CCCUGGCU 3777 AGCCAGGG GGCTAGCTACAACGA CTCCTGAT 10456
162 AGACCCUG G CUAUCAUA 3566 TATGATAG GGCTAGCTACAACGA CAGGGTCT 10457
165 CCCUGGCU A UCAUAGAC 2445 GTCTATGA GGCTAGCTACAACGA AGCCAGGG 10458
168 UGGCUAUC A UAGACCUU 3088 AAGGTCTA GGCTAGCTACAACGA GATAGCCA 10459
172 UAUCAUAG A CCUUAGUC 3778 GACTAAGG GGCTAGCTACAACGA CTATGATA 10460
178 AGACCUUA G UCUUCGCU 3567 AGCGAAGA GGCTAGCTACAACGA TAAGGTCT 10461
184 UAGUCUUC G CUGGUAUA 3568 TATACCAG GGCTAGCTACAACGA GAAGACTA 10462
188 CUUCGCUG G UAUACUCG 3569 CGAGTATA GGCTAGCTACAACGA CAGCGAAG 10463
190 UCGCUGGU A UACUCGCU 2453 AGCGAGTA GGCTAGCTACAACGA ACCAGCGA 10464
192 GCUGGUAU A CUCGCUGU 2454 ACAGCGAG GGCTAGCTACAACGA ATACCAGC 10465 196 GUAUACUC G CUGUCUGU 3570 ACAGACAG GGCTAGCTACAACGA GAGTATAC 10466
199 UACUCGCU G UCUGUCAA 3571 TTGACAGA GGCTAGCTACAACGA AGCGAGTA 10467
203 CGCUGUCU G UCAACCAG 3572 CTGGTTGA GGCTAGCTACAACGA AGACAGCG 10468
207 GUCUGUCA A CCAGCGGU 3779 ACCGCTGG GGCTAGCTACAACGA TGACAGAC 10469
211 GUCAACCA G CGGUUGAC 3573 GTCAACCG GGCTAGCTACAACGA TGGTTGAC 10470
214 AACCAGCG G UUGACUUU 3574 AAAGTCAA GGCTAGCTACAACGA CGCTGGTT 10471
218 AGCGGUUG A CUUUUUUU 3780 AAAAAAAG GGCTAGCTACAACGA CAACCGCT 10472
229 UUUUUUAA G CCUUCUUU 3575 AAAGAAGG GGCTAGCTACAACGA TTAAAAAA 10473
248 UCUCUUUU A CCAGUUUC 2478 GAAACTGG GGCTAGCTACAACGA AAAAGAGA 10474
252 UUUUACCA G UUUCUGGA 3576 TCCAGAAA GGCTAGCTACAACGA TGGTAAAA 10475
261 UUUCUGGA G CAAAUUCA 3577 TGAATTTG GGCTAGCTACAACGA TCCAGAAA 10476
265 UGGAGCAA A UUCAGUUU 3781 AAACTGAA GGCTAGCTACAACGA TTGCTCCA 10477
270 CAAAUUCA G UUUGCCUU 3578 AAGGCAAA GGCTAGCTACAACGA TGAATTTG 10478
274 UUCAGUUU G CCUUCCUG 3579 CAGGAAGG GGCTAGCTACAACGA AAACTGAA 10479
284 CUUCCUGG A UUUGUAAA 3782 TTTACAAA GGCTAGCTACAACGA CCAGGAAG 10480
288 CUGGAUUU G UAAAUUGU 3580 ACAATTTA GGCTAGCTACAACGA AAATCCAG 10481
292 AUUUGUAA A UUGUAAUG 3783 CATTACAA GGCTAGCTACAACGA TTACAAAT 10482
295 UGUAAAUU G UAAUGACC 3581 GGTCATTA GGCTAGCTACAACGA AATTTACA 10483
298 AAAUUGUA A UGACCUCA 3784 TGAGGTCA GGCTAGCTACAACGA TACAATTT 10484
301 UUGUAAUG A CCUCAAAA 3785 TTTTGAGG GGCTAGCTACAACGA CATTACAA 10485
309 ACCUCAAA A CUUUAGCA 3786 TGCTAAAG GGCTAGCTACAACGA TTTGAGGT 10486
315 AAACUUUA G CAGUUCUU 3582 AAGAACTG GGCTAGCTACAACGA TAAAGTTT 10487
318 CUUUAGCA G UUCUUCCA 3583 TGGAAGAA GGCTAGCTACAACGA TGCTAAAG 10488
326 GUUCUUCC A UCUGACUC 3121 GAGTCAGA GGCTAGCTACAACGA GGAAGAAC 10489
331 UCCAUCUG A CUCAGGUU 3787 AACCTGAG GGCTAGCTACAACGA CAGATGGA 10490
337 UGACUCAG G UUUGCUUC 3584 GAAGCAAA GGCTAGCTACAACGA CTGAGTCA 10491
341 UCAGGUUU G CUUCUCUG 3585 CAGAGAAG GGCTAGCTACAACGA AAACCTGA 10492
350 CUUCUCUG G CGGUCUUC 3586 GAAGACCG GGCTAGCTACAACGA CAGAGAAG 10493
353 CUCUGGCG G UCUUCAGA 3587 TCTGAAGA GGCTAGCTACAACGA CGCCAGAG 10494
362 UCUUCAGA A UCAACAUC 3788 GATGTTGA GGCTAGCTACAACGA TCTGAAGA 10495
366 CAGAAUCA A CAUCCACA 3789 TGTGGATG GGCTAGCTACAACGA TGATTCTG 10496
368 GAAUCAAC A UCCACACU 3131 AGTGTGGA GGCTAGCTACAACGA GTTGATTC 10497
372 CAACAUCC A CACUUCCG 3133 CGGAAGTG GGCTAGCTACAACGA GGATGTTG 10498
374 ACAUCCAC A CUUCCGUG 3134 CACGGAAG GGCTAGCTACAACGA GTGGATGT 10499
380 ACACUUCC G UGAUUAUC 3588 GATAATCA GGCTAGCTACAACGA GGAAGTGT 10500
383 CUUCCGUG A UUAUCUGC 3790 GCAGATAA GGCTAGCTACAACGA CACGGAAG 10501
386 CCGUGAUU A UCUGCGUG 2516 CACGCAGA GGCTAGCTACAACGA AATCACGG 10502
390 GAUUAUCU G CGUGCAUU 3589 AATGCACG GGCTAGCTACAACGA AGATAATC 10503
392 UUAUCUGC G UGCAUUUU 3590 AAAATGCA GGCTAGCTACAACGA GCAGATAA 10504
394 AUCUGCGU G CAUUUUGG 3591 CCAAAATG GGCTAGCTACAACGA ACGCAGAT 10505
396 CUGCGUGC A UUUUGGAC 3138 GTCCAAAA GGCTAGCTACAACGA GCACGCAG 10506
403 CAUUUUGG A CAAAGCUU 3791 AAGCTTTG GGCTAGCTACAACGA CCAAAATG 10507
408 UGGACAAA G CUUCCAAC 3592 GTTGGAAG GGCTAGCTACAACGA TTTGTCCA 10508
415 AGCUUCCA A CCAGGAUA 3792 TATCCTGG GGCTAGCTACAACGA TGGAAGCT 10509
421 CAACCAGG A UACGGGAA 3793 TTCCCGTA GGCTAGCTACAACGA CCTGGTTG 10510
423 ACCAGGAU A CGGGAAGA 2523 TCTTCCCG GGCTAGCTACAACGA ATCCTGGT 10511
436 AAGAAGAA A UGGCUGGU 3794 ACCAGCCA GGCTAGCTACAACGA TTCTTCTT 10512
439 AAGAAAUG G CUGGUGAU 3593 ATCACCAG GGCTAGCTACAACGA CATTTCTT 10513
443 AAUGGCUG G UGAUCUUU 3594 AAAGATCA GGCTAGCTACAACGA CAGCCATT 10514
446 GGCUGGUG A UCUUUCAG 3795 CTGAAAGA GGCTAGCTACAACGA CACCAGCC 10515
454 AUCUUUCA G CAGGUUUC 3595 GAAACCTG GGCTAGCTACAACGA TGAAAGAT 10516 458 UUCAGCAG G UUUCUUCA 3596 TGAAGAAA GGCTAGCTACAACGA CTGCTGAA 10517
466 GUUUCUUC A UGGAGGAA 3150 TTCCTCCA GGCTAGCTACAACGA GAAGAAAC 10518
474 AUGGAGGA A CUUAAUAC 3796 GTATTAAG GGCTAGCTACAACGA TCCTCCAT 10519
479 GGAACUUA A UACAUACC 3797 GGTATGTA GGCTAGCTACAACGA TAAGTTCC 10520
481 AACUUAAU A CAUACCGU 2535 ACGGTATG GGCTAGCTACAACGA ATTAAGTT 10521
483 CUUAAUAC A UACCGUCA 3152 TGACGGTA GGCTAGCTACAACGA GTATTAAG 10522
485 UAAUACAU A CCGUCAGA 2536 TCTGACGG GGCTAGCTACAACGA ATGTATTA 10523
488 UACAUACC G UCAGAAGC 3597 GCTTCTGA GGCTAGCTACAACGA GGTATGTA 10524
495 CGUCAGAA G CAGGGAGU 3598 ACTCCCTG GGCTAGCTACAACGA TTCTGACG 10525
502 AGCAGGGA G UAGUACUU 3599 AAGTACTA GGCTAGCTACAACGA TCCCTGCT 10526
505 AGGGAGUA G UACUUAAA 3600 TTTAAGTA GGCTAGCTACAACGA TACTCCCT 10527
507 GGAGUAGU A CUUAAAUA 2539 TATTTAAG GGCTAGCTACAACGA ACTACTCC 10528
513 GUACUUAA A UAUCAAGA 3798 TCTTGATA GGCTAGCTACAACGA TTAAGTAC 10529
515 ACUUAAAU A UCAAGAAC 2542 GTTCTTGA GGCTAGCTACAACGA ATTTAAGT 10530
522 UAUCAAGA A CUGCCUAA 3799 TTAGGCAG GGCTAGCTACAACGA TCTTGATA 10531
525 CAAGAACU G CCUAAUUC 3601 GAATTAGG GGCTAGCTACAACGA AGTTCTTG 10532
530 ACUGCCUA A UUCAGGAC 3800 GTCCTGAA GGCTAGCTACAACGA TAGGCAGT 10533
537 AAUUCAGG A CCUCCACA 3801 TGTGGAGG GGCTAGCTACAACGA CCTGAATT 10534
543 GGACCUCC A CAUGAUAG 3165 CTATCATG GGCTAGCTACAACGA GGAGGTCC 10535
545 ACCUCCAC A UGAUAGGA 3166 TCCTATCA GGCTAGCTACAACGA GTGGAGGT 10536
548 UCCACAUG A UAGGAGGU 3802 ACCTCCTA GGCTAGCTACAACGA CATGTGGA 10537
555 GAUAGGAG G UUUACAUU 3602 AATGTAAA GGCTAGCTACAACGA CTCCTATC 10538
559 GGAGGUUU A CAUUUCAA 2551 TTGAAATG GGCTAGCTACAACGA AAACCTCC 10539
561 AGGUUUAC A UUUCAAGU 3167 ACTTGAAA GGCTAGCTACAACGA GTAAACCT 10540
568 CAUUUCAA G UUAUAAUA 3603 TATTATAA GGCTAGCTACAACGA TTGAAATG 10541
571 UUCAAGUU A UAAUAGAU 2556 ATCTATTA GGCTAGCTACAACGA AACTTGAA 10542
574 AAGUUAUA A UAGAUGGA 3803 TCCATCTA GGCTAGCTACAACGA TATAACTT 10543
578 UAUAAUAG A UGGAAGAG 3804 CTCTTCCA GGCTAGCTACAACGA CTATTATA 10544
588 GGAAGAGA A UUUCCAGA 3805 TCTGGAAA GGCTAGCTACAACGA TCTCTTCC 10545
599 UCCAGAAG G UGAAGGUA 3604 TACCTTCA GGCTAGCTACAACGA CTTCTGGA 10546
605 AGGUGAAG G UAGAUCAA 3605 TTGATCTA GGCTAGCTACAACGA CTTCACCT 10547
609 GAAGGUAG A UCAAAGAA 3806 TTCTTTGA GGCTAGCTACAACGA CTACCTTC 10548
622 AGAAGGAA G CAAAAAAU 3606 ATTTTTTG GGCTAGCTACAACGA TTCCTTCT 10549
629 AGCAAAAA A UGCCGCAG 3807 CTGCGGCA GGCTAGCTACAACGA TTTTTGCT 10550
631 CAAAAAAU G CCGCAGCC 3607 GGCTGCGG GGCTAGCTACAACGA ATTTTTTG 10551
634 AAAAUGCC G CAGCCAAA 3608 TTTGGCTG GGCTAGCTACAACGA GGCATTTT 10552
637 AUGCCGCA G CCAAAUUA 3609 TAATTTGG GGCTAGCTACAACGA TGCGGCAT 10553
642 GCAGCCAA A UUAGCUGU 3808 ACAGCTAA GGCTAGCTACAACGA TTGGCTGC 10554
646 CCAAAUUA G CUGUUGAG 3610 CTCAACAG GGCTAGCTACAACGA TAATTTGG 10555
649 AAUUAGCU G UUGAGAUA 3611 TATCTCAA GGCTAGCTACAACGA AGCTAATT 10556
655 CUGUUGAG A UACUUAAU 3809 ATTAAGTA GGCTAGCTACAACGA CTCAACAG 10557
657 GUUGAGAU A CUUAAUAA 2567 TTATTAAG GGCTAGCTACAACGA ATCTCAAC 10558
662 GAUACUUA A UAAGGAAA 3810 TTTCCTTA GGCTAGCTACAACGA TAAGTATC 10559
676 AAAAGAAG G CAGUUAGU 3612 ACTAACTG GGCTAGCTACAACGA CTTCTTTT 10560
679 AGAAGGCA G UUAGUCCU 3613 AGGACTAA GGCTAGCTACAACGA TGCCTTCT 10561
683 GGCAGUUA G UCCUUUAU 3614 ATAAAGGA GGCTAGCTACAACGA TAACTGCC 10562
690 AGUCCUUU A UUAUUGAC 2576 GTCAATAA GGCTAGCTACAACGA AAAGGACT 10563
693 CCUUUAUU A UUGACAAC 2578 GTTGTCAA GGCTAGCTACAACGA AATAAAGG 10564
697 UAUUAUUG A CAACAACG 3811 CGTTGTTG GGCTAGCTACAACGA CAATAATA 10565
700 UAUUGACA A CAACGAAU 3812 ATTCGTTG GGCTAGCTACAACGA TGTCAATA 10566
703 UGACAACA A CGAAUUCU 3813 AGAATTCG GGCTAGCTACAACGA TGTTGTCA 10567 707 AACAACGA A UUCUUCAG 3814 CTGAAGAA GGCTAGCTACAACGA TCGTTGTT 10568
720 UCAGAAGG A UUAUCCAU 3815 ATGGATAA GGCTAGCTACAACGA CCTTCTGA 10569
723 GAAGGAUU A UCCAUGGG 2585 CCCATGGA GGCTAGCTACAACGA AATCCTTC 10570
727 GAUUAUCC A UGGGGAAU 3187 ATTCCCCA GGCTAGCTACAACGA GGATAATC 10571
734 CAUGGGGA A UUACAUAG 3816 CTATGTAA GGCTAGCTACAACGA TCCCCATG 10572
737 GGGGAAUU A CAUAGGCC 2588 GGCCTATG GGCTAGCTACAACGA AATTCCCC 10573
739 GGAAUUAC A UAGGCCUU 3188 AAGGCCTA GGCTAGCTACAACGA GTAATTCC 10574
743 UUACAUAG G CCUUAUCA 3615 TGATAAGG GGCTAGCTACAACGA CTATGTAA 10575
748 UAGGCCUU A UCAAUAGA 2591 TCTATTGA GGCTAGCTACAACGA AAGGCCTA 10576
752 CCUUAUCA A UAGAAUUG 3817 CAATTCTA GGCTAGCTACAACGA TGATAAGG 10577
757 UCAAUAGA A UUGCCCAG 3818 CTGGGCAA GGCTAGCTACAACGA TCTATTGA 10578
760 AUAGAAUU G CCCAGAAG 3616 CTTCTGGG GGCTAGCTACAACGA AATTCTAT 10579
774 AAGAAAAG A CUAACUGU 3819 ACAGTTAG GGCTAGCTACAACGA CTTTTCTT 10580
778 AAAGACUA A CUGUAAAU 3820 ATTTACAG GGCTAGCTACAACGA TAGTCTTT 10581
781 GACUAACU G UAAAUUAU 3617 ATAATTTA GGCTAGCTACAACGA AGTTAGTC 10582
785 AACUGUAA A UUAUGAAC 3821 GTTCATAA GGCTAGCTACAACGA TTACAGTT 10583
788 UGUAAAUU A UGAACAGU 2598 ACTGTTCA GGCTAGCTACAACGA AATTTACA 10584
792 AAUUAUGA A CAGUGUGC 3822 GCACACTG GGCTAGCTACAACGA TCATAATT 10585
795 UAUGAACA G UGUGCAUC 3618 GATGCACA GGCTAGCTACAACGA TGTTCATA 10586
797 UGAACAGU G UGCAUCGG 3619 CCGATGCA GGCTAGCTACAACGA ACTGTTCA 10587
799 AACAGUGU G CAUCGGGG 3620 CCCCGATG GGCTAGCTACAACGA ACACTGTT 10588
801 CAGUGUGC A UCGGGGGU 3198 ACCCCCGA GGCTAGCTACAACGA GCACACTG 10589
808 CAUCGGGG G UGCAUGGG 3621 CCCATGCA GGCTAGCTACAACGA CCCCGATG 10590
810 UCGGGGGU G CAUGGGCC 3622 GGCCCATG GGCTAGCTACAACGA ACCCCCGA 10591
812 GGGGGUGC A UGGGCCAG 3199 CTGGCCCA GGCTAGCTACAACGA GCACCCCC 10592
816 GUGCAUGG G CCAGAAGG 3623 CCTTCTGG GGCTAGCTACAACGA CCATGCAC 10593
825 CCAGAAGG A UUUCAUUA 3823 TAATGAAA GGCTAGCTACAACGA CCTTCTGG 10594
830 AGGAUUUC A UUAUAAAU 3202 ATTTATAA GGCTAGCTACAACGA GAAATCCT 10595
833 AUUUCAUU A UAAAUGCA 2604 TGCATTTA GGCTAGCTACAACGA AATGAAAT 10596
837 CAUUAUAA A UGCAAAAU 3824 ATTTTGCA GGCTAGCTACAACGA TTATAATG 10597
839 UUAUAAAU G CAAAAUGG 3624 CCATTTTG GGCTAGCTACAACGA ATTTATAA 10598
844 AAUGCAAA A UGGGACAG 3825 CTGTCCCA GGCTAGCTACAACGA TTTGCATT 10599
849 AAAAUGGG A CAGAAAGA 3826 TCTTTCTG GGCTAGCTACAACGA CCCATTTT 10600
858 CAGAAAGA A UAUAGUAU 3827 ATACTATA GGCTAGCTACAACGA TCTTTCTG 10601
860 GAAAGAAU A UAGUAUUG 2606 CAATACTA GGCTAGCTACAACGA ATTCTTTC 10602
863 AGAAUAUA G UAUUGGUA 3625 TACCAATA GGCTAGCTACAACGA TATATTCT 10603
865 AAUAUAGU A UUGGUACA 2608 TGTACCAA GGCTAGCTACAACGA ACTATATT 10604
869 UAGUAUUG G UACAGGUU 3626 AACCTGTA GGCTAGCTACAACGA CAATACTA 10605
871 GUAUUGGU A CAGGUUCU 2610 AGAACCTG GGCTAGCTACAACGA ACCAATAC 10606
875 UGGUACAG G UUCUACUA 3627 TAGTAGAA GGCTAGCTACAACGA CTGTACCA 10607
880 CAGGUUCU A CUAAACAG 2613 CTGTTTAG GGCTAGCTACAACGA AGAACCTG 10608
885 UCUACUAA A CAGGAAGC 3828 GCTTCCTG GGCTAGCTACAACGA TTAGTAGA 10609
892 AACAGGAA G CAAAACAA 3628 TTGTTTTG GGCTAGCTACAACGA TTCCTGTT 10610
897 GAAGCAAA A CAAUUGGC 3829 GCCAATTG GGCTAGCTACAACGA TTTGCTTC 10611
900 GCAAAACA A UUGGCCGC 3830 GCGGCCAA GGCTAGCTACAACGA TGTTTTGC 10612
904 AACAAUUG G CCGCUAAA 3629 TTTAGCGG GGCTAGCTACAACGA CAATTGTT 10613
907 AAUUGGCC G CUAAACUU 3630 AAGTTTAG GGCTAGCTACAACGA GGCCAATT 10614
912 GCCGCUAA A CUUGCAUA 3831 TATGCAAG GGCTAGCTACAACGA TTAGCGGC 10615
916 CUAAACUU G CAUAUCUU 3631 AAGATATG GGCTAGCTACAACGA AAGTTTAG 10616
918 AAACUUGC A UAUCUUCA 3214 TGAAGATA GGCTAGCTACAACGA GCAAGTTT 10617
920 ACUUGCAU A UCUUCAGA 2618 TCTGAAGA GGCTAGCTACAACGA ATGCAAGT 10618 928 AUCUUCAG A UAUUAUCA 3832 TGATAATA GGCTAGCTACAACGA CTGAAGAT 10619
930 CUUCAGAU A UUAUCAGA 2622 TCTGATAA GGCTAGCTACAACGA ATCTGAAG 10620
933 CAGAUAUU A UCAGAAGA 2624 TCTTCTGA GGCTAGCTACAACGA AATATCTG 10621
943 CAGAAGAA A CCUCAGUG 3833 CACTGAGG GGCTAGCTACAACGA TTCTTCTG 10622
949 AAACCUCA G UGAAAUCU 3632 AGATTTCA GGCTAGCTACAACGA TGAGGTTT 10623
954 UCAGUGAA A UCUGACUA 3834 TAGTCAGA GGCTAGCTACAACGA TTCACTGA 10624
959 GAAAUCUG A CUACCUGU 3835 ACAGGTAG GGCTAGCTACAACGA CAGATTTC 10625
962 AUCUGACU A CCUGUCCU 2628 AGGACAGG GGCTAGCTACAACGA AGTCAGAT 10626
966 GACUACCU G UCCUCUGG 3633 CCAGAGGA GGCTAGCTACAACGA AGGTAGTC 10627
974 GUCCUCUG G UUCUUUUG 3634 CAAAAGAA GGCTAGCTACAACGA CAGAGGAC 10628
982 GUUCUUUU G CUACUACG 3635 CGTAGTAG GGCTAGCTACAACGA AAAAGAAC 10629
985 CUUUUGCU A CUACGUGU 2636 ACACGTAG GGCTAGCTACAACGA AGCAAAAG 10630
988 UUGCUACU A CGUGUGAG 2637 CTCACACG GGCTAGCTACAACGA AGTAGCAA 10631
990 GCUACUAC G UGUGAGUC 3636 GACTCACA GGCTAGCTACAACGA GTAGTAGC 10632
992 UACUACGU G UGAGUCCC 3637 GGGACTCA GGCTAGCTACAACGA ACGTAGTA 10633
996 ACGUGUGA G UCCCAAAG 3638 CTTTGGGA GGCTAGCTACAACGA TCACACGT 10634
1004 GUCCCAAA G CAACUCUU 3639 AAGAGTTG GGCTAGCTACAACGA TTTGGGAC 10635
1007 CCAAAGCA A CUCUUUAG 3836 CTAAAGAG GGCTAGCTACAACGA TGCTTTGG 10636
1015 ACUCUUUA G UGACCAGC 3640 GCTGGTCA GGCTAGCTACAACGA TAAAGAGT 10637
1018 CUUUAGUG A CCAGCACA 3837 TGTGCTGG GGCTAGCTACAACGA CACTAAAG 10638
1022 AGUGACCA G CACACUCG 3641 CGAGTGTG GGCTAGCTACAACGA TGGTCACT 10639
1024 UGACCAGC A CACUCGCU 3239 AGCGAGTG GGCTAGCTACAACGA GCTGGTCA 10640
1026 ACCAGCAC A CUCGCUUC 3240 GAAGCGAG GGCTAGCTACAACGA GTGCTGGT 10641
1030 GCACACUC G CUUCUGAA 3642 TTCAGAAG GGCTAGCTACAACGA GAGTGTGC 10642
1038 GCUUCUGA A UCAUCAUC 3838 GATGATGA GGCTAGCTACAACGA TCAGAAGC 10643
1041 UCUGAAUC A UCAUCUGA 3244 TCAGATGA GGCTAGCTACAACGA GATTCAGA 10644
1044 GAAUCAUC A UCUGAAGG 3245 CCTTCAGA GGCTAGCTACAACGA GATGATTC 10645
1052 AUCUGAAG G UGACUUCU 3643 AGAAGTCA GGCTAGCTACAACGA CTTCAGAT 10646
1055 UGAAGGUG A CUUCUCAG 3839 CTGAGAAG GGCTAGCTACAACGA CACCTTCA 10647
1063 ACUUCUCA G CAGAUACA 3644 TGTATCTG GGCTAGCTACAACGA TGAGAAGT 10648
1067 CUCAGCAG A UACAUCAG 3840 CTGATGTA GGCTAGCTACAACGA CTGCTGAG 10649
1069 CAGCAGAU A CAUCAGAG 2652 CTCTGATG GGCTAGCTACAACGA ATCTGCTG 10650
1071 GCAGAUAC A UCAGAGAU 3251 ATCTCTGA GGCTAGCTACAACGA GTATCTGC 10651
1078 CAUCAGAG A UAAAUUCU 3841 AGAATTTA GGCTAGCTACAACGA CTCTGATG 10652
1082 AGAGAUAA A UUCUAACA 3842 TGTTAGAA GGCTAGCTACAACGA TTATCTCT 10653
1088 AAAUUCUA A CAGUGACA 3843 TGTCACTG GGCTAGCTACAACGA TAGAATTT 10654
1091 UUCUAACA G UGACAGUU 3645 AACTGTCA GGCTAGCTACAACGA TGTTAGAA 10655
1094 UAACAGUG A CAGUUUAA 3844 TTAAACTG GGCTAGCTACAACGA CACTGTTA 10656
1097 CAGUGACA G UUUAAACA 3646 TGTTTAAA GGCTAGCTACAACGA TGTCACTG 10657
1103 CAGUUUAA A CAGUUCUU 3845 AAGAACTG GGCTAGCTACAACGA TTAAACTG 10658
1106 UUUAAACA G UUCUUCGU 3647 ACGAAGAA GGCTAGCTACAACGA TGTTTAAA 10659
1113 AGUUCUUC G UUGCUUAU 3648 ATAAGCAA GGCTAGCTACAACGA GAAGAACT 10660
1116 UCUUCGUU G CUUAUGAA 3649 TTCATAAG GGCTAGCTACAACGA AACGAAGA 10661
1120 CGUUGCUU A UGAAUGGU 2667 ACCATTCA GGCTAGCTACAACGA AAGCAACG 10662
1124 GCUUAUGA A UGGUCUCA 3846 TGAGACCA GGCTAGCTACAACGA TCATAAGC 10663
1127 UAUGAAUG G UCUCAGAA 3650 TTCTGAGA GGCTAGCTACAACGA CATTCATA 10664
1136 UCUCAGAA A UAAUCAAA 3847 TTTGATTA GGCTAGCTACAACGA TTCTGAGA 10665
1139 CAGAAAUA A UCAAAGGA 3848 TCCTTTGA GGCTAGCTACAACGA TATTTCTG 10666
1150 AAAGGAAG G CAAAAAGA 3651 TCTTTTTG GGCTAGCTACAACGA CTTCCTTT 10667
1158 GCAAAAAG A UCUUUGGC 3849 GCCAAAGA GGCTAGCTACAACGA CTTTTTGC 10668
1165 GAUCUUUG G CACCCAGA 3652 TCTGGGTG GGCTAGCTACAACGA CAAAGATC 10669 1167 UCUUUGGC A CCCAGAUU 3264 AATCTGGG GGCTAGCTACAACGA GCCAAAGA 10670
1173 GCACCCAG A UUUGACCU 3850 AGGTCAAA GGCTAGCTACAACGA CTGGGTGC 10671
1178 CAGAUUUG A CCUUCCUG 3851 CAGGAAGG GGCTAGCTACAACGA CAAATCTG 10672
1187 CCUUCCUG A CAUGAAAG 3852 CTTTCATG GGCTAGCTACAACGA CAGGAAGG 10673
1189 UUCCUGAC A UGAAAGAA 3272 TTCTTTCA GGCTAGCTACAACGA GTCAGGAA 10674
1198 UGAAAGAA A CAAAGUAU 3853 ATACTTTG GGCTAGCTACAACGA TTCTTTCA 10675
1203 GAAACAAA G UAUACUGU 3653 ACAGTATA GGCTAGCTACAACGA TTTGTTTC 10676
1205 AACAAAGU A UACUGUGG 2679 CCACAGTA GGCTAGCTACAACGA ACTTTGTT 10677
1207 CAAAGUAU A CUGUGGAC 2680 GTCCACAG GGCTAGCTACAACGA ATACTTTG 10678
1210 AGUAUACU G UGGACAAG 3654 CTTGTCCA GGCTAGCTACAACGA AGTATACT 10679
1214 UACUGUGG A CAAGAGGU 3854 ACCTCTTG GGCTAGCTACAACGA CCACAGTA 10680
1221 GACAAGAG G UUUGGCAU 3655 ATGCCAAA GGCTAGCTACAACGA CTCTTGTC 10681
1226 GAGGUUUG G CAUGGAUU 3656 AATCCATG GGCTAGCTACAACGA CAAACCTC 10682
1228 GGUUUGGC A UGGAUUUU 3276 AAAATCCA GGCTAGCTACAACGA GCCAAACC 10683
1232 UGGCAUGG A UUUUAAAG 3855 CTTTAAAA GGCTAGCTACAACGA CCATGCCA 10684
1243 UUAAAGAA A UAGAAUUA 3856 TAATTCTA GGCTAGCTACAACGA TTCTTTAA 10685
1248 GAAAUAGA A UUAAUUGG 3857 CCAATTAA GGCTAGCTACAACGA TCTATTTC 10686
1252 UAGAAUUA A UUGGCUCA 3858 TGAGCCAA GGCTAGCTACAACGA TAATTCTA 10687
1256 AUUAAUUG G CUCAGGUG 3657 CACCTGAG GGCTAGCTACAACGA CAATTAAT 10688
1262 UGGCUCAG G UGGAUUUG 3658 CAAATCCA GGCTAGCTACAACGA CTGAGCCA 10689
1266 UCAGGUGG A UUUGGCCA 3859 TGGCCAAA GGCTAGCTACAACGA CCACCTGA 10690
1271 UGGAUUUG G CCAAGUUU 3659 AAACTTGG GGCTAGCTACAACGA CAAATCCA 10691
1276 UUGGCCAA G UUUUCAAA 3660 TTTGAAAA GGCTAGCTACAACGA TTGGCCAA 10692
1285 UUUUCAAA G CAAAACAC 3661 GTGTTTTG GGCTAGCTACAACGA TTTGAAAA 10693
1290 AAAGCAAA A CACAGAAU 3860 ATTCTGTG GGCTAGCTACAACGA TTTGCTTT 10694
1292 AGCAAAAC A CAGAAUUG 3283 CAATTCTG GGCTAGCTACAACGA GTTTTGCT 10695
1297 AACACAGA A UUGACGGA 3861 TCCGTCAA GGCTAGCTACAACGA TCTGTGTT 10696
1301 CAGAAUUG A CGGAAAGA 3862 TCTTTCCG GGCTAGCTACAACGA CAATTCTG 10697
1309 ACGGAAAG A CUUACGUU 3863 AACGTAAG GGCTAGCTACAACGA CTTTCCGT 10698
1313 AAAGACUU A CGUUAUUA 2700 TAATAACG GGCTAGCTACAACGA AAGTCTTT 10699
1315 AGACUUAC G UUAUUAAA 3662 TTTAATAA GGCTAGCTACAACGA GTAAGTCT 10700
1318 CUUACGUU A UUAAACGU 2702 ACGTTTAA GGCTAGCTACAACGA AACGTAAG 10701
1323 GUUAUUAA A CGUGUUAA 3864 TTAACACG GGCTAGCTACAACGA TTAATAAC 10702
1325 UAUUAAAC G UGUUAAAU 3663 ATTTAACA GGCTAGCTACAACGA GTTTAATA 10703
1327 UUAAACGU G UUAAAUAU 3664 ATATTTAA GGCTAGCTACAACGA ACGTTTAA 10704
1332 CGUGUUAA A UAUAAUAA 3865 TTATTATA GGCTAGCTACAACGA TTAACACG 10705
1334 UGUUAAAU A UAAUAACG 2707 CGTTATTA GGCTAGCTACAACGA ATTTAACA 10706
1337 UAAAUAUA A UAACGAGA 3866 TCTCGTTA GGCTAGCTACAACGA TATATTTA 10707
1340 AUAUAAUA A CGAGAAGG 3867 CCTTCTCG GGCTAGCTACAACGA TATTATAT 10708
1348 ACGAGAAG G CGGAGCGU 3665 ACGCTCCG GGCTAGCTACAACGA CTTCTCGT 10709
1353 AAGGCGGA G CGUGAAGU 3666 ACTTCACG GGCTAGCTACAACGA TCCGCCTT 10710
1355 GGCGGAGC G UGAAGUAA 3667 TTACTTCA GGCTAGCTACAACGA GCTCCGCC 10711
1360 AGCGUGAA G UAAAAGCA 3668 TGCTTTTA GGCTAGCTACAACGA TTCACGCT 10712
1366 AAGUAAAA G CAUUGGCA 3669 TGCCAATG GGCTAGCTACAACGA TTTTACTT 10713
1368 GUAAAAGC A UUGGCAAA 3286 TTTGCCAA GGCTAGCTACAACGA GCTTTTAC 10714
1372 AAGCAUUG G CAAAACUU 3670 AAGTTTTG GGCTAGCTACAACGA CAATGCTT 10715
1377 UUGGCAAA A CUUGAUCA 3868 TGATCAAG GGCTAGCTACAACGA TTTGCCAA 10716
1382 AAAACUUG A UCAUGUAA 3869 TTACATGA GGCTAGCTACAACGA CAAGTTTT 10717
1385 ACUUGAUC A UGUAAAUA 3289 TATTTACA GGCTAGCTACAACGA GATCAAGT 10718
1387 UUGAUCAU G UAAAUAUU 3671 AATATTTA GGCTAGCTACAACGA ATGATCAA 10719
1391 UCAUGUAA A UAUUGUUC 3870 GAACAATA GGCTAGCTACAACGA TTACATGA 10720 1393 AUGUAAAU A UUGUUCAC 2715 GTGAACAA GGCTAGCTACAACGA ATTTACAT 10721
1396 UAAAUAUU G UUCACUAC 3672 GTAGTGAA GGCTAGCTACAACGA AATATTTA 10722
1400 UAUUGUUC A CUACAAUG 3290 CATTGTAG GGCTAGCTACAACGA GAACAATA 10723
1403 UGUUCACU A CAAUGGCU 2719 AGCCATTG GGCTAGCTACAACGA AGTGAACA 10724
1406 UCACUACA A UGGCUGUU 3871 AACAGCCA GGCTAGCTACAACGA TGTAGTGA 10725
1409 CUACAAUG G CUGUUGGG 3673 CCCAACAG GGCTAGCTACAACGA CATTGTAG 10726
1412 CAAUGGCU G UUGGGAUG 3674 CATCCCAA GGCTAGCTACAACGA AGCCATTG 10727
1418 CUGUUGGG A UGGAUUUG 3872 CAAATCCA GGCTAGCTACAACGA CCCAACAG 10728
1422 UGGGAUGG A UUUGAUUA 3873 TAATCAAA GGCTAGCTACAACGA CCATCCCA 10729
1427 UGGAUUUG A UUAUGAUC 3874 GATCATAA GGCTAGCTACAACGA CAAATCCA 10730
1430 AUUUGAUU A UGAUCCUG 2724 CAGGATCA GGCTAGCTACAACGA AATCAAAT 10731
1433 UGAUUAUG A UCCUGAGA 3875 TCTCAGGA GGCTAGCTACAACGA CATAATCA 10732
1441 AUCCUGAG A CCAGUGAU 3876 ATCACTGG GGCTAGCTACAACGA CTCAGGAT 10733
1445 UGAGACCA G UGAUGAUU 3675 AATCATCA GGCTAGCTACAACGA TGGTCTCA 10734
1448 GACCAGUG A UGAUUCUC 3877 GAGAATCA GGCTAGCTACAACGA CACTGGTC 10735
1451 CAGUGAUG A UUCUCUUG 3878 CAAGAGAA GGCTAGCTACAACGA CATCACTG 10736
1463 UCUUGAGA G CAGUGAUU 3676 AATCACTG GGCTAGCTACAACGA TCTCAAGA 10737
1466 UGAGAGCA G UGAUUAUG 3677 CATAATCA GGCTAGCTACAACGA TGCTCTCA 10738
1469 GAGCAGUG A UUAUGAUC 3879 GATCATAA GGCTAGCTACAACGA CACTGCTC 10739
1472 CAGUGAUU A UGAUCCUG 2731 CAGGATCA GGCTAGCTACAACGA AATCACTG 10740
1475 UGAUUAUG A UCCUGAGA 3875 TCTCAGGA GGCTAGCTACAACGA CATAATCA 10732
1484 UCCUGAGA A CAGCAAAA 3880 TTTTGCTG GGCTAGCTACAACGA TCTCAGGA 10741
1487 UGAGAACA G CAAAAAUA 3678 TATTTTTG GGCTAGCTACAACGA TGTTCTCA 10742
1493 CAGCAAAA A UAGUUCAA 3881 TTGAACTA GGCTAGCTACAACGA TTTTGCTG 10743
1496 CAAAAAUA G UUCAAGGU 3679 ACCTTGAA GGCTAGCTACAACGA TATTTTTG 10744
1503 AGUUCAAG G UCAAAGAC 3680 GTCTTTGA GGCTAGCTACAACGA CTTGAACT 10745
1510 GGUCAAAG A CUAAGUGC 3882 GCACTTAG GGCTAGCTACAACGA CTTTGACC 10746
1515 AAGACUAA G UGCCUUUU 3681 AAAAGGCA GGCTAGCTACAACGA TTAGTCTT 10747
1517 GACUAAGU G CCUUUUCA 3682 TGAAAAGG GGCTAGCTACAACGA ACTTAGTC 10748
1525 GCCUUUUC A UCCAAAUG 3310 CATTTGGA GGCTAGCTACAACGA GAAAAGGC 10749
1531 UCAUCCAA A UGGAAUUC 3883 GAATTCCA GGCTAGCTACAACGA TTGGATGA 10750
1536 CAAAUGGA A UUCUGUGA 3884 TCACAGAA GGCTAGCTACAACGA TCCATTTG 10751
1541 GGAAUUCU G UGAUAAAG 3683 CTTTATCA GGCTAGCTACAACGA AGAATTCC 10752
1544 AUUCUGUG A UAAAGGGA 3885 TCCCTTTA GGCTAGCTACAACGA CACAGAAT 10753
1552 AUAAAGGG A CCUUGGAA 3886 TTCCAAGG GGCTAGCTACAACGA CCCTTTAT 10754
1560 ACCUUGGA A CAAUGGAU 3887 ATCCATTG GGCTAGCTACAACGA TCCAAGGT 10755
1563 UUGGAACA A UGGAUUGA 3888 TCAATCCA GGCTAGCTACAACGA TGTTCCAA 10756
1567 AACAAUGG A UUGAAAAA 3889 TTTTTCAA GGCTAGCTACAACGA CCATTGTT 10757
1583 AAGAAGAG G CGAGAAAC 3684 GTTTCTCG GGCTAGCTACAACGA CTCTTCTT 10758
1590 GGCGAGAA A CUAGACAA 3890 TTGTCTAG GGCTAGCTACAACGA TTCTCGCC 10759
1595 GAAACUAG A CAAAGUUU 3891 AAACTTTG GGCTAGCTACAACGA CTAGTTTC 10760
1600 UAGACAAA G UUUUGGCU 3685 AGCCAAAA GGCTAGCTACAACGA TTTGTCTA 10761
1606 AAGUUUUG G CUUUGGAA 3686 TTCCAAAG GGCTAGCTACAACGA CAAAACTT 10762
1614 GCUUUGGA A CUCUUUGA 3892 TCAAAGAG GGCTAGCTACAACGA TCCAAAGC 10763
1623 CUCUUUGA A CAAAUAAC 3893 GTTATTTG GGCTAGCTACAACGA TCAAAGAG 10764
1627 UUGAACAA A UAACAAAA 3894 TTTTGTTA GGCTAGCTACAACGA TTGTTCAA 10765
1630 AACAAAUA A CAAAAGGG 3895 CCCTTTTG GGCTAGCTACAACGA TATTTGTT 10766
1639 CAAAAGGG G UGGAUUAU 3687 ATAATCCA GGCTAGCTACAACGA CCCTTTTG 10767
1643 AGGGGUGG A UUAUAUAC 3896 GTATATAA GGCTAGCTACAACGA CCACCCCT 10768
1646 GGUGGAUU A UAUACAUU 2759 AATGTATA GGCTAGCTACAACGA AATCCACC 10769
1648 UGGAUUAU A UACAUUCA 2760 TGAATGTA GGCTAGCTACAACGA ATAATCCA 10770 1650 GAUUAUAU A CAUUCAAA 2761 TTTGAATG GGCTAGCTACAACGA ATATAATC 10771
1652 UUAUAUAC A UUCAAAAA 3324 TTTTTGAA GGCTAGCTACAACGA GTATATAA 10772
1662 UCAAAAAA A UUAAUUCA 3897 TGAATTAA GGCTAGCTACAACGA TTTTTTGA 10773
1666 AAAAAUUA A UUCAUAGA 3898 TCTATGAA GGCTAGCTACAACGA TAATTTTT 10774
1670 AUUAAUUC A UAGAGAUC 3326 GATCTCTA GGCTAGCTACAACGA GAATTAAT 10775
1676 UCAUAGAG A UCUUAAGC 3899 GCTTAAGA GGCTAGCTACAACGA CTCTATGA 10776
1683 GAUCUUAA G CCAAGUAA 3688 TTACTTGG GGCTAGCTACAACGA TTAAGATC 10777
1688 UAAGCCAA G UAAUAUAU 3689 ATATATTA GGCTAGCTACAACGA TTGGCTTA 10778
1691 GCCAAGUA A UAUAUUCU 3900 AGAATATA GGCTAGCTACAACGA TACTTGGC 10779
1693 CAAGUAAU A UAUUCUUA 2773 TAAGAATA GGCTAGCTACAACGA ATTACTTG 10780
1695 AGUAAUAU A UUCUUAGU 2774 ACTAAGAA GGCTAGCTACAACGA ATATTACT 10781
1702 UAUUCUUA G UAGAUACA 3690 TGTATCTA GGCTAGCTACAACGA TAAGAATA 10782
1706 CUUAGUAG A UACAAAAC 3901 GTTTTGTA GGCTAGCTACAACGA CTACTAAG 10783
1708 UAGUAGAU A CAAAACAA 2780 TTGTTTTG GGCTAGCTACAACGA ATCTACTA 10784
1713 GAUACAAA A CAAGUAAA 3902 TTTACTTG GGCTAGCTACAACGA TTTGTATC 10785
1717 CAAAACAA G UAAAGAUU 3691 AATCTTTA GGCTAGCTACAACGA TTGTTTTG 10786
1723 AAGUAAAG A UUGGAGAC 3903 GTCTCCAA GGCTAGCTACAACGA CTTTACTT 10787
1730 GAUUGGAG A CUUUGGAC 3904 GTCCAAAG GGCTAGCTACAACGA CTCCAATC 10788
1737 GACUUUGG A CUUGUAAC 3905 GTTACAAG GGCTAGCTACAACGA CCAAAGTC 10789
1741 UUGGACUU G UAACAUCU 3692 AGATGTTA GGCTAGCTACAACGA AAGTCCAA 10790
1744 GACUUGUA A CAUCUCUG 3906 CAGAGATG GGCTAGCTACAACGA TACAAGTC 10791
1746 CUUGUAAC A UCUCUGAA 3335 TTCAGAGA GGCTAGCTACAACGA GTTACAAG 10792
1757 UCUGAAAA A UGAUGGAA 3907 TTCCATCA GGCTAGCTACAACGA TTTTCAGA 10793
1760 GAAAAAUG A UGGAAAGC 3908 GCTTTCCA GGCTAGCTACAACGA CATTTTTC 10794
1767 GAUGGAAA G CGAACAAG 3693 CTTGTTCG GGCTAGCTACAACGA TTTCCATC 10795
1771 GAAAGCGA A CAAGGAGU 3909 ACTCCTTG GGCTAGCTACAACGA TCGCTTTC 10796
1778 AACAAGGA G UAAGGGAA 3694 TTCCCTTA GGCTAGCTACAACGA TCCTTGTT 10797
1786 GUAAGGGA A CUUUGCGA 3910 TCGCAAAG GGCTAGCTACAACGA TCCCTTAC 10798
1791 GGAACUUU G CGAUACAU 3695 ATGTATCG GGCTAGCTACAACGA AAAGTTCC 10799
1794 ACUUUGCG A UACAUGAG 3911 CTCATGTA GGCTAGCTACAACGA CGCAAAGT 10800
1796 UUUGCGAU A CAUGAGCC 2792 GGCTCATG GGCTAGCTACAACGA ATCGCAAA 10801
1798 UGCGAUAC A UGAGCCCA 3340 TGGGCTCA GGCTAGCTACAACGA GTATCGCA 10802
1802 AUACAUGA G CCCAGAAC 3696 GTTCTGGG GGCTAGCTACAACGA TCATGTAT 10803
1809 AGCCCAGA A CAGAUUUC 3912 GAAATCTG GGCTAGCTACAACGA TCTGGGCT 10804
1813 CAGAACAG A UUUCUUCG 3913 CGAAGAAA GGCTAGCTACAACGA CTGTTCTG 10805
1821 AUUUCUUC G CAAGACUA 3697 TAGTCTTG GGCTAGCTACAACGA GAAGAAAT 10806
1826 UUCGCAAG A CUAUGGAA 3914 TTCCATAG GGCTAGCTACAACGA CTTGCGAA 10807
1829 GCAAGACU A UGGAAAGG 2798 CCTTTCCA GGCTAGCTACAACGA AGTCTTGC 10808
1840 GAAAGGAA G UGGACCUC 3698 GAGGTCCA GGCTAGCTACAACGA TTCCTTTC 10809
1844 GGAAGUGG A CCUCUACG 3915 CGTAGAGG GGCTAGCTACAACGA CCACTTCC 10810
1850 GGACCUCU A CGCUUUGG 2800 CCAAAGCG GGCTAGCTACAACGA AGAGGTCC 10811
1852 ACCUCUAC G CUUUGGGG 3699 CCCCAAAG GGCTAGCTACAACGA GTAGAGGT 10812
1860 GCUUUGGG G CUAAUUCU 3700 AGAATTAG GGCTAGCTACAACGA CCCAAAGC 10813
1864 UGGGGCUA A UUCUUGCU 3916 AGCAAGAA GGCTAGCTACAACGA TAGCCCCA 10814
1870 UAAUUCUU G CUGAACUU 3701 AAGTTCAG GGCTAGCTACAACGA AAGAATTA 10815
1875 CUUGCUGA A CUUCUUCA 3917 TGAAGAAG GGCTAGCTACAACGA TCAGCAAG 10816
1883 ACUUCUUC A UGUAUGUG 3357 CACATACA GGCTAGCTACAACGA GAAGAAGT 10817
1885 UUCUUCAU G UAUGUGAC 3702 GTCACATA GGCTAGCTACAACGA ATGAAGAA 10818
1887 CUUCAUGU A UGUGACAC 2811 GTGTCACA GGCTAGCTACAACGA ACATGAAG 10819
1889 UCAUGUAU G UGACACUG 3703 CAGTGTCA GGCTAGCTACAACGA ATACATGA 10820
1892 UGUAUGUG A CACUGCUU 3918 AAGCAGTG GGCTAGCTACAACGA CACATACA 10821 1894 UAUGUGAC A CUGCUUUU 3358 AAAAGCAG GGCTAGCTACAACGA GTCACATA 10822
1897 GUGACACU G CUUUUGAA 3704 TTCAAAAG GGCTAGCTACAACGA AGTGTCAC 10823
1906 CUUUUGAA A CAUCAAAG 3919 CTTTGATG GGCTAGCTACAACGA TTCAAAAG 10824
1908 UUUGAAAC A UCAAAGUU 3361 AACTTTGA GGCTAGCTACAACGA GTTTCAAA 10825
1914 ACAUCAAA G UUUUUCAC 3705 GTGAAAAA GGCTAGCTACAACGA TTTGATGT 10826
1921 AGUUUUUC A CAGACCUA 3363 TAGGTCTG GGCTAGCTACAACGA GAAAAACT 10827
1925 UUUCACAG A CCUACGGG 3920 CCCGTAGG GGCTAGCTACAACGA CTGTGAAA 10828
1929 ACAGACCU A CGGGAUGG 2821 CCATCCCG GGCTAGCTACAACGA AGGTCTGT 10829
1934 CCUACGGG A UGGCAUCA 3921 TGATGCCA GGCTAGCTACAACGA CCCGTAGG 10830
1937 ACGGGAUG G CAUCAUCU 3706 AGATGATG GGCTAGCTACAACGA CATCCCGT 10831
1939 GGGAUGGC A UCAUCUCA 3367 TGAGATGA GGCTAGCTACAACGA GCCATCCC 10832
1942 AUGGCAUC A UCUCAGAU 3368 ATCTGAGA GGCTAGCTACAACGA GATGCCAT 10833
1949 CAUCUCAG A UAUAUUUG 3922 CAAATATA GGCTAGCTACAACGA CTGAGATG 10834
1951 UCUCAGAU A UAUUUGAU 2825 ATCAAATA GGCTAGCTACAACGA ATCTGAGA 10835
1953 UCAGAUAU A UUUGAUAA 2826 TTATCAAA GGCTAGCTACAACGA ATATCTGA 10836
1958 UAUAUUUG A UAAAAAAG 3923 CTTTTTTA GGCTAGCTACAACGA CAAATATA 10837
1972 AAGAAAAA A CUCUUCUA 3924 TAGAAGAG GGCTAGCTACAACGA TTTTTCTT 10838
1980 ACUCUUCU A CAGAAAUU 2833 AATTTCTG GGCTAGCTACAACGA AGAAGAGT 10839
1986 CUACAGAA A UUACUCUC 3925 GAGAGTAA GGCTAGCTACAACGA TTCTGTAG 10840
1989 CAGAAAUU A CUCUCAAA 2835 TTTGAGAG GGCTAGCTACAACGA AATTTCTG 10841
2001 UCAAAGAA A CCUGAGGA 3926 TCCTCAGG GGCTAGCTACAACGA TTCTTTGA 10842
2009 ACCUGAGG A UCGACCUA 3927 TAGGTCGA GGCTAGCTACAACGA CCTCAGGT 10843
2013 GAGGAUCG A CCUAACAC 3928 GTGTTAGG GGCTAGCTACAACGA CGATCCTC 10844
2018 UCGACCUA A CACAUCUG 3929 CAGATGTG GGCTAGCTACAACGA TAGGTCGA 10845
2020 GACCUAAC A CAUCUGAA 3382 TTCAGATG GGCTAGCTACAACGA GTTAGGTC 10846
2022 CCUAACAC A UCUGAAAU 3383 ATTTCAGA GGCTAGCTACAACGA GTGTTAGG 10847
2029 CAUCUGAA A UACUAAGG 3930 CCTTAGTA GGCTAGCTACAACGA TTCAGATG 10848
2031 UCUGAAAU A CUAAGGAC 2841 GTCCTTAG GGCTAGCTACAACGA ATTTCAGA 10849
2038 UACUAAGG A CCUUGACU 3931 AGTCAAGG GGCTAGCTACAACGA CCTTAGTA 10850
2044 GGACCUUG A CUGUGUGG 3932 CCACACAG GGCTAGCTACAACGA CAAGGTCC 10851
2047 CCUUGACU G UGUGGAAG 3707 CTTCCACA GGCTAGCTACAACGA AGTCAAGG 10852
2049 UUGACUGU G UGGAAGAA 3708 TTCTTCCA GGCTAGCTACAACGA ACAGTCAA 10853
2060 GAAGAAAA G CCCAGAGA 3709 TCTCTGGG GGCTAGCTACAACGA TTTTCTTC 10854
2072 AGAGAAAA A UGAACGAC 3933 GTCGTTCA GGCTAGCTACAACGA TTTTCTCT 10855
2076 AAAAAUGA A CGACACAC 3934 GTGTGTCG GGCTAGCTACAACGA TCATTTTT 10856
2079 AAUGAACG A CACACAUG 3935 CATGTGTG GGCTAGCTACAACGA CGTTCATT 10857
2081 UGAACGAC A CACAUGUU 3392 AACATGTG GGCTAGCTACAACGA GTCGTTCA 10858
2083 AACGACAC A CAUGUUAG 3393 CTAACATG GGCTAGCTACAACGA GTGTCGTT 10859
2085 CGACACAC A UGUUAGAG 3394 CTCTAACA GGCTAGCTACAACGA GTGTGTCG 10860
2087 ACACACAU G UUAGAGCC 3710 GGCTCTAA GGCTAGCTACAACGA ATGTGTGT 10861
2093 AUGUUAGA G CCCUUCUG 3711 CAGAAGGG GGCTAGCTACAACGA TCTAACAT 10862
2107 CUGAAAAA G UAUCCUGC 3712 GCAGGATA GGCTAGCTACAACGA TTTTTCAG 10863
2109 GAAAAAGU A UCCUGCUU 2848 AAGCAGGA GGCTAGCTACAACGA ACTTTTTC 10864
2114 AGUAUCCU G CUUCUGAU 3713 ATCAGAAG GGCTAGCTACAACGA AGGATACT 10865
2121 UGCUUCUG A UAUGCAGU 3936 ACTGCATA GGCTAGCTACAACGA CAGAAGCA 10866
2123 CUUCUGAU A UGCAGUUU 2852 AAACTGCA GGCTAGCTACAACGA ATCAGAAG 10867
2125 UCUGAUAU G CAGUUUUC 3714 GAAAACTG GGCTAGCTACAACGA ATATCAGA 10868
2128 GAUAUGCA G UUUUCCUU 3715 AAGGAAAA GGCTAGCTACAACGA TGCATATC 10869
2139 UUCCUUAA A UUAUCUAA 3937 TTAGATAA GGCTAGCTACAACGA TTAAGGAA 10870
2142 CUUAAAUU A UCUAAAAU 2860 ATTTTAGA GGCTAGCTACAACGA AATTTAAG 10871
2149 UAUCUAAA A UCUGCUAG 3938 CTAGCAGA GGCTAGCTACAACGA TTTAGATA 10872 2153 UAAAAUCU G CUAGGGAA 3716 TTCCCTAG GGCTAGCTACAACGA AGATTTTA 10873
2161 GCUAGGGA A UAUCAAUA 3939 TATTGATA GGCTAGCTACAACGA TCCCTAGC 10874
2163 UAGGGAAU A UCAAUAGA 2865 TCTATTGA GGCTAGCTACAACGA ATTCCCTA 10875
2167 GAAUAUCA A UAGAUAUU 3940 AATATCTA GGCTAGCTACAACGA TGATATTC 10876
2171 AUGAAUAG A UAUUUACC 3941 GGTAAATA GGCTAGCTACAACGA CTATTGAT 10877
2173 CAAUAGAU A UUUACCUU 2868 AAGGTAAA GGCTAGCTACAACGA ATCTATTG 10878
2177 AGAUAUUU A CCUUUUAU 2871 ATAAAAGG GGCTAGCTACAACGA AAATATCT 10879
2184 UACCUUUU A UUUUAAUG 2875 CATTAAAA GGCTAGCTACAACGA AAAAGGTA 10880
2190 UUAUUUUA A UGUUUCCU 3942 AGGAAACA GGCTAGCTACAACGA TAAAATAA 10881
2192 AUUUUAAU G UUUCCUUU 3717 AAAGGAAA GGCTAGCTACAACGA ATTAAAAT 10882
2202 UUCCUUUA A UUUUUUAC 3943 GTAAAAAA GGCTAGCTACAACGA TAAAGGAA 10883
2209 AAUUUUUU A CUAUUUUU 2891 AAAAATAG GGCTAGCTACAACGA AAAAAATT 10884
2212 UUUUUACU A UUUUUACU 2892 AGTAAAAA GGCTAGCTACAACGA AGTAAAAA 10885
2218 CUAUUUUU A CUAAUCUU 2897 AAGATTAG GGCTAGCTACAACGA AAAAATAG 10886
2222 UUUUACUA A UCUUUCUG 3944 CAGAAAGA GGCTAGCTACAACGA TAGTAAAA 10887
2230 AUCUUUCU G CAGAAACA 3718 TGTTTCTG GGCTAGCTACAACGA AGAAAGAT 10888
2236 CUGCAGAA A CAGAAAGG 3945 CCTTTCTG GGCTAGCTACAACGA TTCTGCAG 10889
2244 ACAGAAAG G UUUUCUUC 3719 GAAGAAAA GGCTAGCTACAACGA CTTTCTGT 10890
2258 UUCUUUUU G CUUCAAAA 3720 TTTTGAAG GGCTAGCTACAACGA AAAAAGAA 10891
2267 CUUCAAAA A CAUUCUUA 3946 TAAGAATG GGCTAGCTACAACGA TTTTGAAG 10892
2269 UCAAAAAC A UUCUUACA 3424 TGTAAGAA GGCTAGCTACAACGA GTTTTTGA 10893
2275 ACAUUCUU A CAUUUUAC 2918 GTAAAATG GGCTAGCTACAACGA AAGAATGT 10894
2277 AUUCUUAC A UUUUACUU 3426 AAGTAAAA GGCTAGCTACAACGA GTAAGAAT 10895
2282 UACAUUUU A CUUUUUCC 2922 GGAAAAAG GGCTAGCTACAACGA AAAATGTA 10896
2293 UUUUCCUG G CUCAUCUC 3721 GAGATGAG GGCTAGCTACAACGA CAGGAAAA 10897
2297 CCUGGCUC A UCUCUUUA 3431 TAAAGAGA GGCTAGCTACAACGA GAGCCAGG 10898
2305 AUCUCUUU A UUCUUUUU 2933 AAAAAGAA GGCTAGCTACAACGA AAAGAGAT 10899
2327 UUUUAAAG A CAGAGUCU 3947 AGACTCTG GGCTAGCTACAACGA CTTTAAAA 10900
2332 AAGACAGA G UCUCGCUC 3722 GAGCGAGA GGCTAGCTACAACGA TCTGTCTT 10901
2337 AGAGUCUC G CUCUGUUG 3723 CAACAGAG GGCTAGCTACAACGA GAGACTCT 10902
2342 CUCGCUCU G UUGCCCAG 3724 CTGGGCAA GGCTAGCTACAACGA AGAGCGAG 10903
2345 GCUCUGUU G CCCAGGCU 3725 AGCCTGGG GGCTAGCTACAACGA AACAGAGC 10904
2351 UUGCCCAG G CUGGAGUG 3726 CACTCCAG GGCTAGCTACAACGA CTGGGCAA 10905
2357 AGGCUGGA G UGCAAUGA 3727 TCATTGCA GGCTAGCTACAACGA TCCAGCCT 10906
2359 GCUGGAGU G CAAUGACA 3728 TGTCATTG GGCTAGCTACAACGA ACTCCAGC 10907
2362 GGAGUGCA A UGACACAG 3948 CTGTGTCA GGCTAGCTACAACGA TGCACTCC 10908
2365 GUGCAAUG A CACAGUCU 3949 AGACTGTG GGCTAGCTACAACGA CATTGCAC 10909
2367 GCAAUGAC A CAGUCUUG 3444 CAAGACTG GGCTAGCTACAACGA GTCATTGC 10910
2370 AUGACACA G UCUUGGCU 3729 AGCCAAGA GGCTAGCTACAACGA TGTGTCAT 10911
2376 CAGUCUUG G CUCACUGC 3730 GCAGTGAG GGCTAGCTACAACGA CAAGACTG 10912
2380 CUUGGCUC A CUGCAACU 3448 AGTTGCAG GGCTAGCTACAACGA GAGCCAAG 10913
2383 GGCUCACU G CAACUUCU 3731 AGAAGTTG GGCTAGCTACAACGA AGTGAGCC 10914
2386 UCACUGCA A CUUCUGCC 3950 GGCAGAAG GGCTAGCTACAACGA TGCAGTGA 10915
2392 CAACUUCU G CCUCUUGG 3732 CCAAGAGG GGCTAGCTACAACGA AGAAGTTG 10916
2401 CCUCUUGG G UUCAAGUG 3733 CACTTGAA GGCTAGCTACAACGA CCAAGAGG 10917
2407 GGGUUCAA G UGAUUCUC 3734 GAGAATCA GGCTAGCTACAACGA TTGAACCC 10918
2410 UUCAAGUG A UUCUCCUG 3951 CAGGAGAA GGCTAGCTACAACGA CACTTGAA 10919
2418 AUUCUCCU G CCUCAGCC 3735 GGCTGAGG GGCTAGCTACAACGA AGGAGAAT 10920
2424 CUGCCUCA G CCUCCUGA 3736 TCAGGAGG GGCTAGCTACAACGA TGAGGCAG 10921
2433 CCUCCUGA G UAGCUGGA 3737 TCCAGCTA GGCTAGCTACAACGA TCAGGAGG 10922
2436 CCUGAGUA G CUGGAUUA 3738 TAATCCAG GGCTAGCTACAACGA TACTCAGG 10923 2441 GUAGCUGG A UUACAGGC 3952 GCCTGTAA GGCTAGCTACAACGA CCAGCTAC 10924
2444 GCUGGAUU A CAGGCAUG 2970 CATGCCTG GGCTAGCTACAACGA AATCCAGC 10925
2448 GAUUACAG G CAUGUGCC 3739 GGCACATG GGCTAGCTACAACGA CTGTAATC 10926
2450 UUACAGGC A UGUGCCAC 3469 GTGGCACA GGCTAGCTACAACGA GCCTGTAA 10927
2452 ACAGGCAU G UGCCACCC 3740 GGGTGGCA GGCTAGCTACAACGA ATGCCTGT 10928
2454 AGGCAUGU G CCACCCAC 3741 GTGGGTGG GGCTAGCTACAACGA ACATGCCT 10929
2457 CAUGUGCC A CCCACCCA 3471 TGGGTGGG GGCTAGCTACAACGA GGCACATG 10930
2461 UGCCACCC A CCCAACUA 3474 TAGTTGGG GGCTAGCTACAACGA GGGTGGCA 10931
2466 CCCACCCA A CUAAUUUU 3953 AAAATTAG GGCTAGCTACAACGA TGGGTGGG 10932
2470 CCCAACUA A UUUUUGUG 3954 CACAAAAA GGCTAGCTACAACGA TAGTTGGG 10933
2476 UAAUUUUU G UGUUUUUA 3742 TAAAAACA GGCTAGCTACAACGA AAAAATTA 10934
2478 AUUUUUGU G UUUUUAAU 3743 ATTAAAAA GGCTAGCTACAACGA ACAAAAAT 10935
2485 UGUUUUUA A UAAAGACA 3955 TGTCTTTA GGCTAGCTACAACGA TAAAAACA 10936
2491 UAAUAAAG A CAGGGUUU 3956 AAACCCTG GGCTAGCTACAACGA CTTTATTA 10937
2496 AAGACAGG G UUUCACCA 3744 TGGTGAAA GGCTAGCTACAACGA CCTGTCTT 10938
2501 AGGGUUUC A CCAUGUUG 3480 CAACATGG GGCTAGCTACAACGA GAAACCCT 10939
2504 GUUUCACC A UGUUGGCC 3482 GGCCAACA GGCTAGCTACAACGA GGTGAAAC 10940
2506 UUCACCAU G UUGGCCAG 3745 CTGGCCAA GGCTAGCTACAACGA ATGGTGAA 10941
2510 CCAUGUUG G CCAGGCUG 3746 CAGCCTGG GGCTAGCTACAACGA CAACATGG 10942
2515 UUGGCCAG G CUGGUCUC 3747 GAGACCAG GGCTAGCTACAACGA CTGGCCAA 10943
2519 CCAGGCUG G UCUCAAAC 3748 GTTTGAGA GGCTAGCTACAACGA CAGCCTGG 10944
2526 GGUCUCAA A CUCCUGAC 3957 GTCAGGAG GGCTAGCTACAACGA TTGAGACC 10945
2533 AACUCCUG A CCUCAAGU 3958 ACTTGAGG GGCTAGCTACAACGA CAGGAGTT 10946
2540 GACCUCAA G UAAUCCAC 3749 GTGGATTA GGCTAGCTACAACGA TTGAGGTC 10947
2543 CUCAAGUA A UCCACCUG 3959 CAGGTGGA GGCTAGCTACAACGA TACTTGAG 10948
2547 AGUAAUCC A CCUGCCUC 3495 GAGGCAGG GGCTAGCTACAACGA GGATTACT 10949
2551 AUCCACCU G CCUCGGCC 3750 GGCCGAGG GGCTAGCTACAACGA AGGTGGAT 10950
2557 CUGCCUCG G CCUCCCAA 3751 TTGGGAGG GGCTAGCTACAACGA CGAGGCAG 10951
2567 CUCCCAAA G UGCUGGGA 3752 TCCCAGCA GGCTAGCTACAACGA TTTGGGAG 10952
2569 CCCAAAGU G CUGGGAUU 3753 AATCCCAG GGCTAGCTACAACGA ACTTTGGG 10953
2575 GUGCUGGG A UUACAGGG 3960 CCCTGTAA GGCTAGCTACAACGA CCCAGCAC 10954
2578 CUGGGAUU A CAGGGAUG 2995 CATCCCTG GGCTAGCTACAACGA AATCCCAG 10955
2584 UUACAGGG A UGAGCCAC 3961 GTGGCTCA GGCTAGCTACAACGA CCCTGTAA 10956
2588 AGGGAUGA G CCACCGCG 3754 CGCGGTGG GGCTAGCTACAACGA TCATCCCT 10957
2591 GAUGAGCC A CCGCGCCC 3508 GGGCGCGG GGCTAGCTACAACGA GGCTCATC 10958
2594 GAGCCACC G CGCCCAGC 3755 GCTGGGCG GGCTAGCTACAACGA GGTGGCTC 10959
2596 GCCACCGC G CCCAGCCU 3756 AGGCTGGG GGCTAGCTACAACGA GCGGTGGC 10960
2601 CGCGCCCA G CCUCAUCU 3757 AGATGAGG GGCTAGCTACAACGA TGGGCGCG 10961
2606 CCAGCCUC A UCUCUUUG 3515 CAAAGAGA GGCTAGCTACAACGA GAGGCTGG 10962
2614 AUCUCUUU G UUCUAAAG 3758 CTTTAGAA GGCTAGCTACAACGA AAAGAGAT 10963
2623 UUCUAAAG A UGGAAAAA 3962 TTTTTCCA GGCTAGCTACAACGA CTTTAGAA 10964
2631 AUGGAAAA A CCACCCCC 3963 GGGGGTGG GGCTAGCTACAACGA TTTTCCAT 10965
2634 GAAAAACC A CCCCCAAA 3520 TTTGGGGG GGCTAGCTACAACGA GGTTTTTC 10966
2642 ACCCCCAA A UUUUCUUU 3964 AAAGAAAA GGCTAGCTACAACGA TTGGGGGT 10967
2653 UUCUUUUU A UACUAUUA 3012 TAATAGTA GGCTAGCTACAACGA AAAAAGAA 10968
2655 CUUUUUAU A CUAUUAAU 3013 ATTAATAG GGCTAGCTACAACGA ATAAAAAG 10969
2658 UUUAUACU A UUAAUGAA 3014 TTCATTAA GGCTAGCTACAACGA AGTATAAA 10970
2662 UACUAUUA A UGAAUCAA 3965 TTGATTCA GGCTAGCTACAACGA TAATAGTA 10971
2666 AUUAAUGA A UCAAUCAA 3966 TTGATTGA GGCTAGCTACAACGA TCATTAAT 10972
2670 AUGAAUCA A UCAAUUCA 3967 TGAATTGA GGCTAGCTACAACGA TGATTCAT 10973
2674 AUCAAUCA A UUCAUAUC 3968 GATATGAA GGCTAGCTACAACGA TGATTGAT 10974 2678 AUCAAUUC A UAUCUAUU 3530 AATAGATA GGCTAGCTACAACGA GAATTGAT 10975
2680 CAAUUCAU A UCUAUUUA 3021 TAAATAGA GGCTAGCTACAACGA ATGAATTG 10976
2684 UCAUAUCU A UUUAUUAA 3023 TTAATAAA GGCTAGCTACAACGA AGATATGA 10977
2688 AUCUAUUU A UUAAAUUU 3026 AAATTTAA GGCTAGCTACAACGA AAATAGAT 10978
2693 UUUAUUAA A UUUCUACC 3969 GGTAGAAA GGCTAGCTACAACGA TTAATAAA 10979
2699 AAAUUUCU A CCGCUUUU 3032 AAAAGCGG GGCTAGCTACAACGA AGAAATTT 10980
2702 UUUCUACC G CUUUUAGG 3759 CCTAAAAG GGCTAGCTACAACGA GGTAGAAA 10981
2710 GCUUUUAG G CCAAAAAA 3760 TTTTTTGG GGCTAGCTACAACGA CTAAAAGC 10982
2719 CCAAAAAA A UGUAAGAU 3970 ATCTTACA GGCTAGCTACAACGA TTTTTTGG 10983
2721 AAAAAAAU G UAAGAUCG 3761 CGATCTTA GGCTAGCTACAACGA ATTTTTTT 10984
2726 AAUGUAAG A UCGUUCUC 3971 GAGAACGA GGCTAGCTACAACGA CTTACATT 10985
2729 GUAAGAUC G UUCUCUGC 3762 GCAGAGAA GGCTAGCTACAACGA GATCTTAC 10986
2736 CGUUCUCU G CCUCACAU 3763 ATGTGAGG GGCTAGCTACAACGA AGAGAACG 10987
2741 UCUGCCUC A CAUAGCUU 3541 AAGCTATG GGCTAGCTACAACGA GAGGCAGA 10988
2743 UGCCUCAC A UAGCUUAC 3542 GTAAGCTA GGCTAGCTACAACGA GTGAGGCA 10989
2746 CUCACAUA G CUUACAAG 3764 CTTGTAAG GGCTAGCTACAACGA TATGTGAG 10990
2750 CAUAGCUU A CAAGCCAG 3045 CTGGCTTG GGCTAGCTACAACGA AAGCTATG 10991
2754 GCUUACAA G CCAGCUGG 3765 CCAGCTGG GGCTAGCTACAACGA TTGTAAGC 10992
2758 ACAAGCCA G CUGGAGAA 3766 TTCTCCAG GGCTAGCTACAACGA TGGCTTGT 10993
2767 CUGGAGAA A UAUGGUAC 3972 GTACCATA GGCTAGCTACAACGA TTCTCCAG 10994
2769 GGAGAAAU A UGGUACUC 3046 GAGTACCA GGCTAGCTACAACGA ATTTCTCC 10995
2772 GAAAUAUG G UACUCAUU 3767 AATGAGTA GGCTAGCTACAACGA CATATTTC 10996
2774 AAUAUGGU A CUCAUUAA 3047 TTAATGAG GGCTAGCTACAACGA ACCATATT 10997
2778 UGGUACUC A UUAAAAAA 3549 TTTTTTAA GGCTAGCTACAACGA GAGTACCA 10998
2796 AAAAAAAA G UGAUGUAC 3768 GTACATCA GGCTAGCTACAACGA TTTTTTTT 10999
2799 AAAAAGUG A UGUACAAC 3973 GTTGTACA GGCTAGCTACAACGA CACTTTTT 11000
Input Sequence = NM_002759. Cut Site = R/Y
Arm Length = 8. Core Sequence = GGCTAGCTACAACGA
NM_002759 (Homo sapiens protein kinase, interferon-inducible double stranded RNA dependent (PRKR), mRNA.; 2808 bp)
Table XVII: Human PKR Amberzyme and Substrate Sequence
Pos Substrate Seq Amberzyme Seq ID ID
9 GCGGCGGC G GCGGCGCA 3974 UGCGCCGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCCGCCGC 11001
10 CGGCGGCG G
Figure imgf000225_0001
CGGCGCAG 3550 CUGCGCCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGCCGCCG 11002
12 GCGGCGGC G GCGCAGUU 3975 AACUGCGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCCGCCGC 11003
13 CGGCGGCG G CGCAGUUU 3551 AAACUGCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGCCGCCG 11004
15 GCGGCGGC G CAGUUUGC 3552 GGAAACUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCCGCCGC 11005
18 GCGGCGCA G UUUGCUCA 3553 UGAGCAAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCGCCGC 11006
22 CGCAGUUU G CUCAUACU 3554 AGUAUGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAACUGCG 11007
33 CAUACUUU G UGACUUGC 3555 GCAAGUCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAAGUAUG 11008
35 UACUUUGU G ACUUGCGG 3976 CCGCAAGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACAAAGUA 11009
40 UGUGACUU G CGGUCACA 3556 UGUGACCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAGUCACA 11010
42 UGACUUGC G GUCACAGU 3977 ACUGUGAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCAAGUCA 11011
43 GACUUGCG G UCACAGUG 3557 CACUGUGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGCAAGUC 11012
49 CGGUCACA G UGGCAUUC 3558 GAAUGCCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUGACCG 11013
51 GUCACAGU G GCAUUCAG 3978 CUGAAUGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACUGUGAC 11014
52 UCACAGUG G CAUUCAGC 3559 GCUGAAUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CACUGUGA 11015
59 GGCAUUCA G CUCCACAC 3560 GUGUGGAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGAAUGCC 11016
70 CCACACUU G GUAGAACC 3979 GGUUCUAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAGUGUGG 11017
71 CACACUUG G UAGAACCA 3561 UGGUUCUA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAAGUGUG 11018
74 ACUUGGUA G AACCACAG 3980 CUGUGGUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UACCAAGU 11019
82 GAACCACA G GCACGACA 3981 UGUCGUGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGUGGUUC 11020
83 AACCACAG G CACGACAA 3562 UUGUCGUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUGUGGUU 11021
87 ACAGGCAC G ACAAGCAU 3982 AUGCUUGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GUGCCUGU 11022
92 CACGACAA G CAUAGAAA 3563 UUUCUAUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUGUCGUG 11023
97 CAAGCAUA G AAACAUCC 3983 GGAUGUUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UAUGCUUG 11024
121 UCUUCAUC G AGGCAUCG 3984 CGAUGCCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GAUGAAGA 11025
123 UUCAUCGA G GCAUCGAG 3985 CUCGAUGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCGAUGAA 11026
124 UCAUCGAG G CAUCGAGG 3564 CCUCGAUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUCGAUGA 11027
129 GAGGCAUC G AGGUCCAU 3986 AUGGACCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GAUGCCUC 11028
131 GGCAUCGA G GUCCAUCC 3987 GGAUGGAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCGAUGCC 11029
132 GCAUCGAG G UCCAUCCC 3565 GGGAUGGA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUCGAUGC 11030
152 AAAAAUCA G GAGACCCU 3988 AGGGUCUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGAUUUUU 11031
153 AAAAUCAG G AGACCCUG 3989 CAGGGUCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUGAUUUU 11032
155 AAUCAGGA G ACCCUGGC 3990 GCCAGGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCUGAUU 11033
161 GAGACCCU G GCUAUCAU 3991 AUGAUAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGGUCUC 11034
162 AGACCCUG G CUAUCAUA 3566 UAUGAUAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGGGUCU 11035
171 CUAUCAUA G ACCUUAGU 3992 ACUAAGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UAUGAUAG 11036
178 AGACCUUA G UCUUCGCU 3567 AGCGAAGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UAAGGUCU 11037
184 UAGUCUUC G CUGGUAUA 3568 UAUACCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GAAGACUA 11038
Figure imgf000226_0001
187 UCUUCGCU G GUAUACUC 3993 GAGUAUAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCGAAGA 11039
188 CUUCGCUG G UAUACUCG 3569 CGAGUAUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGCGAAG 11040
196 GUAUACUC G CUGUCUGU 3570 ACAGACAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GAGUAUAC 11041
199 UACUCGCU G UCUGUCAA 3571 UUGACAGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCGAGUA 11042
203 CGCUGUCU G UCAACCAG 3572 CUGGUUGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGACAGCG 11043
211 GUCAACCA G CGGUUGAC 3573 GUCAACCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGUUGAC 11044
213 CAACCAGC G GUUGACUU 3994 AAGUCAAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCUGGUUG 11045
214 AACCAGCG G UUGACUUU 3574 AAAGUCAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGCUGGUU 11046
217 CAGCGGUU G ACUUUUUU 3995 AAAAAAGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AACCGCUG 11047
229 UUUUUUAA G CCUUCUUU 3575 AAAGAAGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUAAAAAA 11048
252 UUUUACCA G UUUCUGGA 3576 UCCAGAAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGUAAAA 11049
258 CAGUUUCU G GAGCAAAU 3996 AUUUGCUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGAAACUG 11050
259 AGUUUCUG G AGCAAAUU 3997 AAUUUGCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGAAACU 11051
261 UUUCUGGA G CAAAUUCA 3577 UGAAUUUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCAGAAA 11052
270 CAAAUUCA G UUUGCCUU 3578 AAGGCAAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGAAUUUG 11053
274 UUCAGUUU G CCUUCCUG 3579 CAGGAAGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAACUGAA 11054
282 GCCUUCCU G GAUUUGUA 3998 UACAAAUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGAAGGC 11055
283 CCUUCCUG G AUUUGUAA 3999 UUACAAAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGGAAGG 11056
288 CUGGAUUU G UAAAUUGU 3580 ACAAUUUA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAAUCCAG 11057
295 UGUAAAUU G UAAUGACC 3581 GGUCAUUA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAUUUACA 11058
300 AUUGUAAU G ACCUCAAA 4000 UUUGAGGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUUACAAU 11059
315 AAACUUUA G CAGUUCUU 3582 AAGAACUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UAAAGUUU 11060
318 CUUUAGCA G UUCUUCCA 3583 UGGAAGAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGCUAAAG 11061
330 UUCCAUCU G ACUCAGGU 4001 ACCUGAGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGAUGGAA 11062
336 CUGACUCA G GUUUGCUU 4002 AAGCAAAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGAGUCAG 11063
337 UGACUCAG G UUUGCUUC 3584 GAAGCAAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUGAGUCA 11064
341 UCAGGUUU G CUUCUCUG 3585 CAGAGAAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAACCUGA 11065
349 GCUUCUCU G GCGGUCUU 4003 AAGACCGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGAGAAGC 11066
350 CUUCUCUG G CGGUCUUC 3586 GAAGACCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGAGAAG 11067
352 UCUCUGGC G GUCUUCAG 4004 CUGAAGAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCCAGAGA 11068
353 CUCUGGCG G UCUUCAGA 3587 UCUGAAGA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGCCAGAG 11069
360 GGUCUUCA G AAUCAACA 4005 UGUUGAUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGAAGACC 11070
380 ACACUUCC G UGAUUAUC 3588 GAUAAUCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGAAGUGU 11071
382 ACUUCCGU G AUUAUCUG 4006 CAGAUAAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACGGAAGU 11072
390 GAUUAUCU G CGUGCAUU 3589 AAUGCACG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAUAAUC 11073
392 UUAUCUGC G UGCAUUUU 3590 AAAAUGCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCAGAUAA 11074
394 AUCUGCGU G CAUUUUGG 3591 CCAAAAUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACGCAGAU 11075
Figure imgf000227_0001
401 UGCAUUUU G GACAAAGC 4007 GCUUUGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAAAUGCA 11076
402 GCAUUUUG G ACAAAGCU 4008 AGCUUUGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAAAAUGC 11077
408 UGGACAAA G CUUCCAAC 3592 GUUGGAAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUGUCCA 11078
419 UCCAACCA G GAUACGGG 4009 CCCGUAUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGUUGGA 11079
420 CCAACCAG G AUACGGGA 4010 UCCCGUAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGGUUGG 11080
425 CAGGAUAC G GGAAGAAG 4011 CUUCUUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GUAUCCUG 11081
426 AGGAUACG G GAAGAAGA 4012 UCUUCUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGUAUCCU 11082
427 GGAUACGG G AAGAAGAA 4013 UUCUUCUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCGUAUCC 11083
430 UACGGGAA G AAGAAAUG 4014 CAUUUCUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUCCCGUA 11084
433 GGGAAGAA G AAAUGGCU 4015 AGCCAUUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUCUUCCC 11085
438 GAAGAAAU G GCUGGUGA 4016 UCACCAGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUUUCUUC 11086
439 AAGAAAUG G CUGGUGAU 3593 AUCACCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAUUUCUU 11087
442 AAAUGGCU G GUGAUCUU 4017 AAGAUCAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCCAUUU 11088
443 AAUGGCUG G UGAUCUUU 3594 AAAGAUCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGCCAUU 11089
445 UGGCUGGU G AUCUUUCA 4018 UGAAAGAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACCAGCCA 11090
454 AUCUUUCA G CAGGUUUC 3595 GAAACCUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGAAAGAU 11091
457 UUUCAGCA G GUUUCUUC 4019 GAAGAAAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGCUGAAA 11092
458 UUCAGCAG G UUUCUUCA 3596 UGAAGAAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUGCUGAA 11093
468 UUCUUCAU G GAGGAACU 4020 AGUUCCUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUGAAGAA 11094
469 UCUUCAUG G AGGAACUU 4021 AAGUUCCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAUGAAGA 11095
471 UUCAUGGA G GAACUUAA 4022 UUAAGUUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCAUGAA 11096
472 UCAUGGAG G AACUUAAU 4023 AUUAAGUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUCCAUGA 11097
488 UACAUACC G UCAGAAGC 3597 GCUUCUGA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGUAUGUA 11098
492 UACCGUCA G AAGCAGGG 4024 CCCUGCUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGACGGUA 11099
495 CGUCAGAA G GAGGGAGU 3598 ACUCCCUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUCUGACG 11100
498 CAGAAGCA G GGAGUAGU 4025 ACUACUCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGCUUCUG 11101
499 AGAAGCAG G GAGUAGUA 4026 UACUACUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUGCUUCU 11102
500 GAAGCAGG G AGUAGUAC 4027 GUACUACU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCUGCUUC 11103
502 AGCAGGGA G UAGUACUU 3599 AAGUACUA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCCUGCU 11104
505 AGGGAGUA G UACUUAAA 3600 UUUAAGUA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UACUCCCU 11105
520 AAUAUCAA G AACUGCCU 4028 AGGCAGUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUGAUAUU 11106
525 CAAGAACU G CCUAAUUC 3601 GAAUUAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGUUCUUG 11107
535 CUAAUUCA G GACCUCGA 4029 UGGAGGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGAAUUAG 11108
536 UAAUUCAG G ACCUCCAC 4030 GUGGAGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGAAUUA 11109
547 CUCCACAU G AUAGGAGG 4031 CCUCCUAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUGUGGAG 11110
551 ACAUGAUA G GAGGUUUA 4032 UAAACCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UAUCAUGU lllll
552 CAUGAUAG G AGGUUUAC 4033 GUAAACCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUAUCAUG 11112
Figure imgf000228_0001
554 UGAUAGGA G GUUUACAU 4034 AUGUAAAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCUAUCA 11113
555 GAUAGGAG G UUUACAUU 3602 AAUGUAAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCCUAUC 11114
568 CAUUUCAA G UUAUAAUA 3603 UAUUAUAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGAAAUG 11115
577 UUAUAAUA G AUGGAAGA 4035 UCUUCCAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UAUUAUAA 11116
580 UAAUAGAU G GAAGAGAA 4036 UUCUCUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUCUAUUA 11117
581 AAUAGAUG G AAGAGAAU 4037 AUUCUCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUCUAUU 11118
584 AGAUGGAA G AGAAUUUC 4038 GAAAUUCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCCAUCU 11119
586 AUGGAAGA G AAUUUCCA 4039 UGGAAAUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUUCCAU 11120
595 AAUUUCCA G AAGGUGAA 4040 UUCACCUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGAAAUU 11121
598 UUCCAGAA G GUGAAGGU 4041 ACCUUCAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUCUGGAA 11122
599 UCCAGAAG G UGAAGGUA 3604 UACCUUCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUUCUGGA 11123
601 CAGAAGGU G AAGGUAGA 4042 UCUACCUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACCUUCUG 11124
604 AAGGUGAA G GUAGAUCA 4043 UGAUCUAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUCACCUU 11125
605 AGGUGAAG G UAGAUCAA 3605 UUGAUCUA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUUCACCU 11126
608 UGAAGGUA G AUCAAAGA 4044 UCUUUGAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UACCUUCA 11127
615 AGAUCAAA G AAGGAAGC 4045 GCUUCCUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUUGAUCU 11128
618 UCAAAGAA G GAAGCAAA 4046 UUUGCUUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUCUUUGA 11129
619 CAAAGAAG G AAGCAAAA 4047 UUUUGCUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUUCUUUG 11130
622 AGAAGGAA G CAAAAAAU 3606 AUUUUUUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUCCUUCU 11131
631 CAAAAAAU G CCGCAGCC 3607 GGCUGCGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUUUUUUG 11132
634 AAAAUGCC G CAGCCAAA 3608 UUUGGCUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGCAUUUU 11133
637 AUGCCGCA G CCAAAUUA 3609 UAAUUUGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGCGGCAU 11134
646 CCAAAUUA G CUGUUGAG 3610 CUCAACAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UAAUUUGG 11135
649 AAUUAGCU G UUGAGAUA 3611 UAUCUCAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCUAAUU 11136
652 UAGCUGUU G AGAUACUU 4048 AAGUAUCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AACAGCUA 11137
654 GCUGUUGA G AUACUUAA 4049 UUAAGUAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCAACAGC 11138
666 CUUAAUAA G GAAAAGAA 4050 UUCUUUUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUAUUAAG 11139
667 UUAAUAAG G AAAAGAAG 4051 CUUCUUUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUUAUUAA 11140
672 AAGGAAAA G AAGGCAGU 4052 ACUGCCUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUUUCCUU 11141
675 GAAAAGAA G GCAGUUAG 4053 CUAACUGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUCUUUUC 11142
676 AAAAGAAG G CAGUUAGU 3612 ACUAACUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUUCUUUU 11143
679 AGAAGGCA G UUAGUCCU 3613 AGGACUAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCCUUCU 11144
683 GGCAGUUA G UCCUUUAU 3614 AUAAAGGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UAACUGCC 11145
696 UUAUUAUU G ACAACAAC 4054 GUUGUUGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAUAAUAA 11146
705 ACAACAAC G AAUUCUUC 4055 GAAGAAUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GUUGUUGU 11147
715 AUUCUUGA G AAGGAUUA 4056 UAAUCCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGAAGAAU 11148
718 CUUCAGAA G GAUUAUCC 4057 GGAUAAUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCUGAAG 11149
Figure imgf000229_0001
719 UUCAGAAG G AUUAUCCA 4058 UGGAUAAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUCUGAA 11150
729 UUAUCCAU G GGGAAUUA 4059 UAAUUCCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUGGAUAA 11151
730 UAUCCAUG G GGAAUUAC 4060 GUAAUUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUGGAUA 11152
731 AUCCAUGG G GAAUUACA 4061 UGUAAUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCAUGGAU 11153
732 UCCAUGGG G AAUUACAU 4062 AUGUAAUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCAUGGA 11154
742 AUUACAUA G GCCUUAUC 4063 GAUAAGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UAUGUAAU 11155
743 UUACAUAG G CCUUAUCA 3615 UGAUAAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUAUGUAA 11156
755 UAUCAAUA G AAUUGCCC 4064 GGGCAAUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UAUUGAUA 11157
760 AUAGAAUU G CCCAGAAG 3616 CUUCUGGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAUUCUAU 11158
765 AUUGCCCA G AAGAAAAG 4065 CUUUUCUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGGCAAU 11159
768 GCCCAGAA G AAAAGACU 4066 AGUCUUUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUCUGGGC 11160
773 GAAGAAAA G ACUAACUG 4067 CAGUUAGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUUUCUUC 11161
781 GACUAACU G UAAAUUAU 3617 AUAAUUUA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGUUAGUC 11162
790 UAAAUUAU G AACAGUGU 4068 ACACUGUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUAAUUUA 11163
795 UAUGAACA G UGUGCAUC 3618 GAUGCACA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGUUCAUA 11164
797 UGAACAGU G UGCAUCGG 3619 CCGAUGCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACUGUUCA 11165
799 AACAGUGU G CAUCGGGG 3620 CCCCGAUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACACUGUU 11166
804 UGUGCAUC G GGGGUGCA 4069 UGCACCCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GAUGCACA 11167
805 GUGCAUCG G GGGUGCAU 4070 AUGCACCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGAUGCAC 11168
806 UGCAUCGG G GGUGCAUG 4071 CAUGCACC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCGAUGCA 11169
807 GCAUCGGG G GUGCAUGG 4072 CCAUGCAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCCGAUGC 11170
808 CAUCGGGG G UGCAUGGG 3621 CCCAUGCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCCCGAUG 11171
810 UCGGGGGU G CAUGGGCC 3622 GGCCCAUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACCCCCGA 11172
814 GGGUGCAU G GGCCAGAA 4073 UUCUGGCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUGCACCC 11173
815 GGUGCAUG G GCCAGAAG 4074 CUUCUGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAUGCACC 11174
816 GUGCAUGG G CCAGAAGG 3623 CCUUCUGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCAUGCAC 11175
820 AUGGGCCA G AAGGAUUU 4075 AAAUCCUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGCCCAU 11176
823 GGCCAGAA G GAUUUCAU 4076 AUGAAAUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUCUGGCC 11177
824 GCCAGAAG G AUUUCAUU 4077 AAUGAAAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUUCUGGC 11178
839 UUAUAAAU G CAAAAUGG 3624 CCAUUUUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUUUAUAA 11179
846 UGCAAAAU G GGACAGAA 4078 UUCUGUCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUUUUGCA 11180
847 GCAAAAUG G GACAGAAA 4079 UUUCUGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUUUUGC 11181
848 CAAAAUGG G ACAGAAAG 4080 CUUUCUGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCAUUUUG 11182
852 AUGGGACA G AAAGAAUA 4081 UAUUCUUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUCCCAU 11183
856 GACAGAAA G AAUAUAGU 4082 ACUAUAUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUCUGUC 11184
863 AGAAUAUA G UAUUGGUA 3625 UACCAAUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UAUAUUCU 11185
868 AUAGUAUU G GUACAGGU 4083 ACCUGUAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAUACUAU 11186
Figure imgf000230_0001
869 UAGUAUUG G UACAGGUU 3626 AACCUGUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAAUACUA 11187
874 UUGGUACA G GUUCUACU 4084 AGUAGAAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUACCAA 11188
875 UGGUACAG G UUCUACUA 3627 UAGUAGAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGUACCA 11189
888 ACUAAACA G GAAGCAAA 4085 UUUGCUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUUUAGU 11190
889 CUAAACAG G AAGCAAAA 4086 UUUUGCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGUUUAG 11191
892 AACAGGAA G CAAAACAA 3628 UUGUUUUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCCUGUU 11192
903 AAACAAUU G GCCGCUAA 4087 UUAGCGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAUUGUUU 11193
904 AACAAUUG G CCGCUAAA 3629 UUUAGCGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAAUUGUU 11194
907 AAUUGGCC G CUAAACUU 3630 AAGUUUAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGCCAAUU 11195
916 CUAAACUU G CAUAUCUU 3631 AAGAUAUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAGUUUAG 11196
927 UAUCUUCA G AUAUUAUC 4088 GAUAAUAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGAAGAUA 11197
937 UAUUAUCA G AAGAAACC 4089 GGUUUCUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGAUAAUA 11198
940 UAUCAGAA G AAACCUCA 4090 UGAGGUUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUCUGAUA 11199
949 AAACCUCA G UGAAAUCU 3632 AGAUUUCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGAGGUUU 11200
951 ACCUCAGU G AAAUCUGA 4091 UCAGAUUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACUGAGGU 11201
958 UGAAAUCU G ACUACCUG 4092 CAGGUAGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGAUUUCA 11202
966 GACUACCU G UCCUCUGG 3633 CCAGAGGA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGUAGUC 11203
973 UGUCCUCU G GUUCUUUU 4093 AAAAGAAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGAGGACA 11204
974 GUCCUCUG G UUCUUUUG 3634 CAAAAGAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGAGGAC 11205
982 GUUCUUUU G CUACUACG 3635 CGUAGUAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAAAGAAC 11206
990 GCUACUAC G UGUGAGUC 3636 GACUCACA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GUAGUAGC 11207
992 UACUACGU G UGAGUCCC 3637 GGGACUCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACGUAGUA 11208
994 CUACGUGU G AGUCCCAA 4094 UUGGGACU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACACGUAG 11209
996 ACGUGUGA G UCCCAAAG 3638 CUUUGGGA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCACACGU 11210
1004 GUCCCAAA G CAACUCUU 3639 AAGAGUUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUUGGGAC 11211
1015 ACUCUUUA G UGACCAGC 3640 GCUGGUCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UAAAGAGU 11212
1017 UCUUUAGU G ACCAGCAC 4095 GUGCUGGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACUAAAGA 11213
1022 AGUGACCA G CACACUCG 3641 CGAGUGUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGUCACU 11214
1030 GCACACUC G CUUCUGAA 3642 UUCAGAAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GAGUGUGC 11215
1036 UCGCUUCU G AAUCAUCA 4096 UGAUGAUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGAAGCGA 11216
1048 CAUCAUCU G AAGGUGAC 4097 GUCACCUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGAUGAUG 11217
1051 CAUCUGAA G GUGACUUC 4098 GAAGUCAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCAGAUG 11218
1052 AUCUGAAG G UGACUUCU 3643 AGAAGUCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUCAGAU 11219
1054 CUGAAGGU G ACUUCUCA 4099 UGAGAAGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACCUUCAG 11220
1063 ACUUCUCA G CAGAUACA 3644 UGUAUCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGAGAAGU 11221
1066 UCUCAGCA G AUACAUCA 4100 UGAUGUAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCUGAGA 11222
1075 AUACAUGA G AGAUAAAU 4101 AUUUAUCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGAUGUAU 11223
Figure imgf000231_0001
1077 ACAUCAGA G AUAAAUUC 4102 GAAUUUAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUGAUGU 11224
1091 UUCUAACA G UGACAGUU 3645 AACUGUCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUUAGAA 11225
1093 CUAACAGU G ACAGUUUA 4103 UAAACUGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACUGUUAG 11226
1097 CAGUGACA G UUUAAACA 3646 UGUUUAAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUCACUG 11227
1106 UUUAAACA G UUCUUCGU 3647 ACGAAGAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUUUAAA 11228
1113 AGUUCUUC G UUGCUUAU 3648 AUAAGCAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GAAGAACU 11229
1116 UCUUCGUU G CUUAUGAA 3649 UUCAUAAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AACGAAGA 11230
1122 UUGCUUAU G AAUGGUCU 4104 AGACCAUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUAAGCAA 11231
1126 UUAUGAAU G GUCUCAGA 4105 UCUGAGAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUUCAUAA 11232
1127 UAUGAAUG G UCUCAGAA 3650 UUCUGAGA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAUUCAUA 11233
1133 UGGUCUCA G AAAUAAUC 4106 GAUUAUUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGAGACCA 11234
1145 UAAUCAAA G GAAGGCAA 4107 UUGCCUUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUUGAUUA 11235
1146 AAUCAAAG G AAGGCAAA 4108 UUUGCCUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUUUGAUU 11236
1149 CAAAGGAA G GCAAAAAG 4109 CUUUUUGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUCCUUUG 11237
1150 AAAGGAAG G CAAAAAGA 3651 UCUUUUUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUUCCUUU 11238
1157 GGCAAAAA G AUCUUUGG 4110 CCAAAGAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUUUUGCC 11239
1164 AGAUCUUU G GCACCCAG 4111 CUGGGUGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAAGAUCU 11240
1165 GAUCUUUG G CACCCAGA 3652 UCUGGGUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAAAGAUC 11241
1172 GGCACCCA G AUUUGACC 4112 GGUCAAAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGGUGCC 11242
1177 CCAGAUUU G ACCUUCCU 4113 AGGAAGGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAAUCUGG 11243
1186 ACCUUCCU G ACAUGAAA 4114 UUUCAUGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGAAGGU 11244
1191 CCUGACAU G AAAGAAAC 4115 GUUUCUUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUGUCAGG 11245
1195 ACAUGAAA G AAACAAAG 4116 CUUUGUUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUUCAUGU 11246
1203 GAAACAAA G UAUACUGU 3653 ACAGUAUA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUUGUUUC 11247
1210 AGUAUACU G UGGACAAG 3654 CUUGUCCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGUAUACU 11248
1212 UAUACUGU G GACAAGAG 4117 CUCUUGUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACAGUAUA 11249
1213 AUACUGUG G ACAAGAGG 4118 CCUCUUGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CACAGUAU 11250
1218 GUGGACAA G AGGUUUGG 4119 CCAAACCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUGUCCAC 11251
1220 GGACAAGA G GUUUGGCA 4120 UGCCAAAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCUUGUCC 11252
1221 GACAAGAG G UUUGGCAU 3655 AUGCCAAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUCUUGUC 11253
1225 AGAGGUUU G GCAUGGAU 4121 AUCCAUGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAACCUCU 11254
1226 GAGGUUUG G CAUGGAUU 3656 AAUCCAUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAAACCUC 11255
1230 UUUGGCAU G GAUUUUAA 4122 UUAAAAUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUGCCAAA 11256
1231 UUGGCAUG G AUUUUAAA 4123 UUUAAAAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUGCCAA 11257
1240 AUUUUAAA G AAAUAGAA 4124 UUCUAUUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUAAAAU 11258
1246 AAGAAAUA G AAUUAAUU 4125 AAUUAAUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UAUUUCUU 11259
1255 AAUUAAUU G GCUCAGGU 4126 ACCUGAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAUUAAUU 11260
Figure imgf000232_0001
1256 AUUAAUUG G CUCAGGUG 3657 CACCUGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAAUUAAU 11261
1261 UUGGCUCA G GUGGAUUU 4127 AAAUCCAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGAGCCAA 11262
1262 UGGCUCAG G UGGAUUUG 3658 CAAAUCCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGAGCCA 11263
1264 GCUCAGGU G GAUUUGGC 4128 GCCAAAUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACCUGAGC 11264
1265 CUCAGGUG G AUUUGGCC 4129 GGCCAAAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CACCUGAG 11265
1270 GUGGAUUU G GCCAAGUU 4130 AACUUGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAAUCCAC 11266
1271 UGGAUUUG G CCAAGUUU 3659 AAACUUGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAAAUCCA 11267
1276 UUGGCCAA G UUUUCAAA 3660 UUUGAAAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUGGCCAA 11268
1285 UUUUCAAA G CAAAACAC 3661 GUGUUUUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUUGAAAA 11269
1295 AAAACACA G AAUUGACG 4131 CGUCAAUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGUGUUUU 11270
1300 ACAGAAUU G ACGGAAAG 4132 CUUUCCGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAUUCUGU 11271
1303 GAAUUGAC G GAAAGACU 4133 AGUCUUUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GUCAAUUC 11272
1304 AAUUGACG G AAAGACUU 4134 AAGUCUUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGUCAAUU 11273
1308 GACGGAAA G ACUUACGU 4135 ACGUAAGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUUCCGUC 11274
1315 AGACUUAC G UUAUUAAA 3662 UUUAAUAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GUAAGUCU 11275
1325 UAUUAAAC G UGUUAAAU 3663 AUUUAACA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GUUUAAUA 11276
1327 UUAAACGU G UUAAAUAU 3664 AUAUUUAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACGUUUAA 11277
1342 AUAAUAAC G AGAAGGCG 4136 CGCCUUCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GUUAUUAU 11278
1344 AAUAACGA G AAGGCGGA 4137 UCCGCCUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCGUUAUU 11279
1347 AACGAGAA G GCGGAGCG 4138 CGCUCCGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUCUCGUU 11280
1348 ACGAGAAG G CGGAGCGU 3665 ACGCUCCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUUCUCGU 11281
1350 GAGAAGGC G GAGCGUGA 4139 UCACGCUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCCUUCUC 11282
1351 AGAAGGCG G AGCGUGAA 4140 UUCACGCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGCCUUCU 11283
1353 AAGGCGGA G CGUGAAGU 3666 ACUUCACG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCGCCUU 11284
1355 GGCGGAGC G UGAAGUAA 3667 UUACUUCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCUCCGCC 11285
1357 CGGAGCGU G AAGUAAAA 4141 UUUUACUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACGCUCCG 11286
1360 AGCGUGAA G UAAAAGCA 3668 UGCUUUUA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUCACGCU 11287
1366 AAGUAAAA G CAUUGGCA 3669 UGCCAAUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUUUACUU 11288
1371 AAAGCAUU G GCAAAACU 4142 AGUUUUGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAUGCUUU 11289
1372 AAGCAUUG G CAAAACUU 3670 AAGUUUUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAAUGCUU 11290
1381 CAAAACUU G AUCAUGUA 4143 UACAUGAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAGUUUUG 11291
1387 UUGAUCAU G UAAAUAUU 3671 AAUAUUUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUGAUCAA 11292
1396 UAAAUAUU G UUCACUAC 3672 GUAGUGAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAUAUUUA 11293
1408 ACUACAAU G GCUGUUGG 4144 CCAACAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUUGUAGU 11294
1409 CUACAAUG G CUGUUGGG 3673 CCCAACAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUUGUAG 11295
1412 CAAUGGCU G UUGGGAUG 3674 CAUCCCAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCCAUUG 11296
1415 UGGCUGUU G GGAUGGAU 4145 AUCCAUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AACAGCCA 11297
Figure imgf000233_0001
1416 GGCUGUUG G GAUGGAUU 4146 AAUCCAUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAACAGCC 11298
1417 GCUGUUGG G AUGGAUUU 4147 AAAUCCAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCAACAGC 11299
1420 GUUGGGAU G GAUUUGAU 4148 AUCAAAUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUCCCAAC 11300
1421 UUGGGAUG G AUUUGAUU 4149 AAUCAAAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUCCCAA 11301
1426 AUGGAUUU G AUUAUGAU 4150 AUCAUAAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAAUCCAU 11302
1432 UUGAUUAU G AUCCUGAG 4151 CUCAGGAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUAAUCAA 11303
1438 AUGAUCCU G AGACCAGU 4152 ACUGGUCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGAUCAU 11304
1440 GAUCCUGA G ACCAGUGA 4153 UCACUGGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCAGGAUC 11305
1445 UGAGACCA G UGAUGAUU 3675 AAUCAUCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGUCUCA 11306
1447 AGACCAGU G AUGAUUCU 4154 AGAAUCAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACUGGUCU 11307
1450 CCAGUGAU G AUUCUCUU 4155 AAGAGAAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUCACUGG 11308
1459 AUUCUCUU G AGAGCAGU 4156 ACUGCUCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAGAGAAU 11309
1461 UCUCUUGA G AGCAGUGA 4157 UCACUGCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCAAGAGA 11310
1463 UCUUGAGA G CAGUGAUU 3676 AAUCACUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCUCAAGA 11311
1466 UGAGAGCA G UGAUUAUG 3677 CAUAAUCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGCUCUCA 11312
1468 AGAGCAGU G AUUAUGAU 4158 AUCAUAAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACUGCUCU 11313
1474 GUGAUUAU G AUCCUGAG 4159 CUCAGGAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUAAUCAC 11314
1480 AUGAUCCU G AGAACAGC 4160 GCUGUUCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGAUCAU 11315
1482 GAUCCUGA G AACAGCAA 4161 UUGCUGUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCAGGAUC 11316
1487 UGAGAACA G CAAAAAUA 3678 UAUUUUUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGUUCUCA 11317
1496 CAAAAAUA G UUCAAGGU 3679 ACCUUGAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UAUUUUUG 11318
1502 UAGUUCAA G GUCAAAGA 4162 UCUUUGAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUGAACUA 11319
1503 AGUUCAAG G UCAAAGAC 3680 GUCUUUGA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUUGAACU 11320
1509 AGGUCAAA G ACUAAGUG 4163 CACUUAGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUUGACCU 11321
1515 AAGACUAA G UGCCUUUU 3681 AAAAGGCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUAGUCUU 11322
1517 GACUAAGU G CCUUUUCA 3682 UGAAAAGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACUUAGUC 11323
1533 AUCCAAAU G GAAUUCUG 4164 CAGAAUUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUUUGGAU 11324
1534 UCCAAAUG G AAUUCUGU 4165 ACAGAAUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAUUUGGA 11325
1541 GGAAUUCU G UGAUAAAG 3683 CUUUAUCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGAAUUCC 11326
1543 AAUUCUGU G AUAAAGGG 4166 CCCUUUAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACAGAAUU 11327
1549 GUGAUAAA G GGACCUUG 4167 CAAGGUCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUUAUCAC 11328
1550 UGAUAAAG G GACCUUGG 4168 CCAAGGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUUAUCA 11329
1551 GAUAAAGG G ACCUUGGA 4169 UCCAAGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCUUUAUC 11330
1557 GGGACCUU G GAACAAUG 4170 CAUUGUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAGGUCCC 11331
1558 GGACCUUG G AACAAUGG 4171 CCAUUGUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAAGGUCC 11332
1565 GGAACAAU G GAUUGAAA 4172 UUUCAAUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUUGUUCC 11333
1566 GAACAAUG G AUUGAAAA 4173 UUUUCAAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUUGUUC 11334
Figure imgf000234_0001
1570 AAUGGAUU G AAAAAAGA 4174 UCUUUUUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAUCCAUU 11335
1577 UGAAAAAA G AAGAGGCG 4175 CGCCUCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUUUUCA 11336
1580 AAAAAGAA G AGGCGAGA 4176 UCUCGCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCUUUUU 11337
1582 AAAGAAGA G GCGAGAAA 4177 UUUCUCGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUUCUUU 11338
1583 AAGAAGAG G CGAGAAAC 3684 GUUUCUCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG cucuucuu 11339
1585 GAAGAGGC G AGAAACUA 4178 UAGUUUCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCCUCUUC 11340
1587 AGAGGCGA G AAACUAGA 4179 UCUAGUUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCGCCUCU 11341
1594 AGAAACUA G ACAAAGUU 4180 AACUUUGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UAGUUUCU 11342
1600 UAGACAAA G UUUUGGCU 3685 AGCCAAAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUUGUCUA 11343
1605 AAAGUUUU G GCUUUGGA 4181 UCCAAAGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAAACUUU 11344
1606 AAGUUUUG G CUUUGGAA 3686 UUCCAAAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAAAACUU 11345
1611 UUGGCUUU G GAACUCUU 4182 AAGAGUUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAAGCCAA 11346
1612 UGGCUUUG G AACUCUUU 4183 AAAGAGUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAAAGCCA 11347
1621 AACUCUUU G AACAAAUA 4184 UAUUUGUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAAGAGUU 11348
1636 UAACAAAA G GGGUGGAU 4185 AUCCACCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUUUGUUA 11349
1637 AACAAAAG G GGUGGAUU 4186 AAUCCACC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUUUUGUU 11350
1638 ACAAAAGG G GUGGAUUA 4187 UAAUCCAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCUUUUGU 11351
1639 CAAAAGGG G UGGAUUAU 3687 AUAAUCCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCCUUUUG 11352
1641 AAAGGGGU G GAUUAUAU 4188 AUAUAAUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACCCCUUU 11353
1642 AAGGGGUG G AUUAUAUA 4189 UAUAUAAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CACCCCUU 11354
1673 AAUUCAUA G AGAUCUUA 4190 UAAGAUCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UAUGAAUU 11355
1675 UUCAUAGA G AUCUUAAG 4191 CUUAAGAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCUAUGAA 11356
1683 GAUCUUAA G CCAAGUAA 3688 UUACUUGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUAAGAUC 11357
1688 UAAGCCAA G UAAUAUAU 3689 AUAUAUUA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUGGCUUA 11358
1702 UAUUCUUA G UAGAUACA 3690 UGUAUCUA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UAAGAAUA 11359
1705 UCUUAGUA G AUACAAAA 4192 UUUUGUAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UACUAAGA 11360
1717 CAAAACAA G UAAAGAUU 3691 AAUCUUUA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUGUUUUG 11361
1722 CAAGUAAA G AUUGGAGA 4193 UCUCCAAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUUACUUG 11362
1726 UAAAGAUU G GAGACUUU 4194 AAAGUCUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAUCUUUA 11363
1727 AAAGAUUG G AGACUUUG 4195 CAAAGUCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAAUCUUU 11364
1729 AGAUUGGA G ACUUUGGA 4196 UCCAAAGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCAAUCU 11365
1735 GAGACUUU G GACUUGUA 4197 UACAAGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAAGUCUC 11366
1736 AGACUUUG G ACUUGUAA 4198 UUACAAGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAAAGUCU 11367
1741 UUGGACUU G UAACAUCU 3692 AGAUGUUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAGUCCAA 11368
1752 ACAUCUCU G AAAAAUGA 4199 UCAUUUUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAGAUGU 11369
1759 UGAAAAAU G AUGGAAAG 4200 CUUUCCAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUUUUUCA 11370
1762 AAAAUGAU G GAAAGCGA 4201 UCGCUUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUCAUUUU 11371
Figure imgf000235_0001
1763 AAAUGAUG G AAAGCGAA 4202 UUCGCUUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUCAUUU 11372
1767 GAUGGAAA G CGAACAAG 3693 CUUGUUCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUCCAUC 11373
1769 UGGAAAGC G AACAAGGA 4203 UCCUUGUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCUUUCCA 11374
1775 GCGAACAA G GAGUAAGG 4204 CCUUACUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGUUCGC 11375
1776 CGAACAAG G AGUAAGGG 4205 CCCUUACU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUGUUCG 11376
1778 AAGAAGGA G UAAGGGAA 3694 UUCCCUUA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCUUGUU 11377
1782 AGGAGUAA G GGAACUUU 4206 AAAGUUCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUACUCCU 11378
1783 GGAGUAAG G GAACUUUG 4207 CAAAGUUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUUACUCC 11379
1784 GAGUAAGG G AACUUUGC 4208 GCAAAGUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCUUACUC 11380
1791 GGAACUUU G CGAUACAU 3695 AUGUAUCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAAGUUCC 11381
1793 AACUUUGC G AUACAUGA 4209 UCAUGUAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCAAAGUU 11382
1800 CGAUACAU G AGCCCAGA 4210 UCUGGGCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUGUAUCG 11383
1802 AUACAUGA G CCCAGAAC 3696 GUUCUGGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCAUGUAU 11384
1807 UGAGCCCA G AACAGAUU 4211 AAUCUGUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGGCUCA 11385
1812 CCAGAACA G AUUUCUUC 4212 GAAGAAAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGUUCUGG 11386
1821 AUUUCUUC G CAAGACUA 3697 UAGUCUUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GAAGAAAU 11387
1825 CUUCGCAA G ACUAUGGA 4213 UCCAUAGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUGCGAAG 11388
1831 AAGACUAU G GAAAGGAA 4214 UUCCUUUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUAGUCUU 11389
1832 AGACUAUG G AAAGGAAG 4215 CUUCCUUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAUAGUCU 11390
1836 UAUGGAAA G GAAGUGGA 4216 UCCACUUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUUCCAUA 11391
1837 AUGGAAAG G AAGUGGAC 4217 GUCCACUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUUUCCAU 11392
1840 GAAAGGAA G UGGACCUC 3698 GAGGUCCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUCCUUUC 11393
1842 AAGGAAGU G GACCUCUA 4218 UAGAGGUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACUUCCUU 11394
1843 AGGAAGUG G ACCUCUAC 4219 GUAGAGGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CACUUCCU 11395
1852 ACCUCUAC G CUUUGGGG 3699 CCCCAAAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GUAGAGGU 11396
1857 UACGCUUU G GGGCUAAU 220 AUUAGCCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAAGCGUA 11397
1858 ACGCUUUG G GGCUAAUU 4221 AAUUAGCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAAAGCGU 11398
1859 CGCUUUGG G GCUAAUUC 4222 GAAUUAGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCAAAGCG 11399
1860 GCUUUGGG G CUAAUUCU 3700 AGAAUUAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCCAAAGC 11400
1870 UAAUUCUU G CUGAACUU 3701 AAGUUCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAGAAUUA 11401
1873 UUCUUGCU G AACUUCUU 4223 AAGAAGUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCAAGAA 11402
1885 UUCUUCAU G UAUGUGAC 3702 GUCACAUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUGAAGAA 11403
1889 UCAUGUAU G UGACACUG 3703 CAGUGUCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUACAUGA 11404
1891 AUGUAUGU G ACACUGCU 4224 AGCAGUGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACAUACAU 11405
1897 GUGACACU G CUUUUGAA 3704 UUCAAAAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGUGUCAC 11406
1903 CUGCUUUU G AAACAUCA 4225 UGAUGUUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAAAGCAG 11407
1914 ACAUGAAA G UUUUUCAC 3705 GUGAAAAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUGAUGU 11408
Figure imgf000236_0001
1924 UUUUCACA G ACCUACGG 4226 CCGUAGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUGAAAA 11409
1931 AGACCUAC G GGAUGGCA 4227 UGCCAUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GUAGGUCU 11410
1932 GACCUACG G GAUGGCAU 4228 AUGCCAUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGUAGGUC 11411
1933 ACCUACGG G AUGGCAUC 4229 GAUGCCAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCGUAGGU 11412
1936 UACGGGAU G GCAUCAUC 4230 GAUGAUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUCCCGUA 11413
1937 ACGGGAUG G CAUCAUCU 3706 AGAUGAUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUCCCGU 11414
1948 UCAUCUCA G AUAUAUUU 4231 AAAUAUAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGAGAUGA 11415
1957 AUAUAUUU G AUAAAAAA 4232 UUUUUUAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAAUAUAU 11416
1966 AUAAAAAA G AAAAAACU 4233 AGUUUUUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUUUUUAU 11417
1983 CUUCUACA G AAAUUACU 4234 AGUAAUUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGUAGAAG 11418
1998 CUCUCAAA G AAACCUGA 4235 UCAGGUUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUUGAGAG 11419
2005 AGAAACCU G AGGAUCGA 4236 UCGAUCCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGUUUCU 11420
2007 AAACCUGA G GAUCGACC 4237 GGUCGAUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCAGGUUU 11421
2008 AACCUGAG G AUCGACCU 4238 AGGUCGAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUCAGGUU 11422
2012 UGAGGAUC G ACCUAACA 4239 UGUUAGGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GAUCCUCA 11423
2026 ACACAUCU G AAAUACUA 4240 UAGUAUUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGAUGUGU 11424
2036 AAUACUAA G GACCUUGA 4241 UCAAGGUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUAGUAUU 11425
2037 AUACUAAG G ACCUUGAC 4242 GUCAAGGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUUAGUAU 11426
2043 AGGACCUU G ACUGUGUG 4243 CACACAGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAGGUCCU 11427
2047 CCUUGACU G UGUGGAAG 3707 CUUCCACA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGUCAAGG 11428
2049 UUGACUGU G UGGAAGAA 3708 UUCUUCCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACAGUCAA 11429
2051 GACUGUGU G GAAGAAAA 4244 UUUUCUUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACACAGUC 11430
2052 ACUGUGUG G AAGAAAAG 4245 CUUUUCUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CACACAGU 11431
2055 GUGUGGAA G AAAAGCCC 4246 GGGCUUUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUCCACAC 11432
2060 GAAGAAAA G CCCAGAGA 3709 UCUCUGGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUUUCUUC 11433
2065 AAAGCCCA G AGAAAAAU 4247 AUUUUUCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGGCUUU 11434
2067 AGCCCAGA G AAAAAUGA 4248 UCAUUUUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCUGGGCU 11435
2074 AGAAAAAU G AACGACAC 4249 GUGUCGUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUUUUUCU 11436
2078 AAAUGAAC G ACACACAU 4250 AUGUGUGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GUUCAUUU 11437
2087 ACACACAU G UUAGAGCC 3710 GGCUCUAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUGUGUGU 11438
2091 AGAUGUUA G AGCCCUUC 4251 GAAGGGCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UAACAUGU 11439
2093 AUGUUAGA G CCCUUCUG 3711 CAGAAGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUAACAU 11440
2101 GCCCUUCU G AAAAAGUA 4252 UACUUUUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAAGGGC 11441
2107 CUGAAAAA G UAUCCUGC 3712 GCAGGAUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUUUCAG 11442
2114 AGUAUCCU G CUUCUGAU 3713 AUCAGAAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGAUACU 11443
2120 CUGCUUCU G AUAUGCAG 4253 CUGCAUAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAAGCAG 11444
2125 UCUGAUAU G CAGUUUUC 3714 GAAAACUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUAUCAGA 11445
Figure imgf000237_0001
2128 GAUAUGCA G UUUUCCUU 3715 AAGGAAAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCAUAUC 11446
2153 UAAAAUCU G CUAGGGAA 3716 UUCCCUAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAUUUUA 11447
2157 AUCUGCUA G GGAAUAUC 4254 GAUAUUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UAGCAGAU 11448
2158 UCUGCUAG G GAAUAUCA 4255 UGAUAUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUAGCAGA 11449
2159 CUGCUAGG G AAUAUCAA 4256 UUGAUAUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCUAGCAG 11450
2170 UAUCAAUA G AUAUUUAC 4257 GUAAAUAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UAUUGAUA 11451
2192 AUUUUAAU G UUUCCUUU 3717 AAAGGAAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUUAAAAU 11452
2230 AUCUUUCU G CAGAAACA 3718 UGUUUCUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGAAAGAU 11453
2233 UUUCUGCA G AAACAGAA 4258 UUCUGUUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGCAGAAA 11454
2239 CAGAAACA G AAAGGUUU 4259 AAACCUUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGUUUCUG 11455
2243 AACAGAAA G GUUUUCUU 4260 AAGAAAAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUUCUGUU 11456
2244 ACAGAAAG G UUUUCUUC 3719 GAAGAAAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUUUCUGU 11457
2258 UUCUUUUU G CUUCAAAA 3720 UUUUGAAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAAAAGAA 11458
2292 UUUUUCCU G GCUCAUCU 4261 AGAUGAGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGAAAAA 11459
2293 UUUUCCUG G CUCAUCUC 3721 GAGAUGAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGGAAAA 11460
2326 UUUUUAAA G ACAGAGUC 4262 GACUCUGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUUAAAAA 11461
2330 UAAAGACA G AGUCUCGC 4263 GCGAGACU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGUCUUUA 11462
2332 AAGACAGA G UCUCGCUC 3722 GAGCGAGA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCUGUCUU 11463
2337 AGAGUCUC G CUCUGUUG 3723 CAACAGAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GAGACUCU 11464
2342 CUCGCUCU G UUGCCCAG 3724 CUGGGCAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGAGCGAG 11465
2345 GCUCUGUU G CCCAGGCU 3725 AGCCUGGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AACAGAGC 11466
2350 GUUGCCCA G GCUGGAGU 4264 ACUCCAGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGGCAAC 11467
2351 UUGCCCAG G CUGGAGUG 3726 CACUCCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUGGGCAA 11468
2354 CCCAGGCU G GAGUGCAA 4265 UUGCACUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCCUGGG 11469
2355 CCAGGCUG G AGUGCAAU 4266 AUUGCACU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGCCUGG 11470
2357 AGGCUGGA G UGCAAUGA 3727 UCAUUGCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCAGCCU 11471
2359 GCUGGAGU G CAAUGACA 3728 UGUCAUUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACUCCAGC 11472
2364 AGUGCAAU G ACACAGUC 4267 GACUGUGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUUGCACU 11473
2370 AUGACACA G UCUUGGCU 3729 AGCCAAGA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGUGUCAU 11474
2375 ACAGUCUU G GCUCACUG 4268 CAGUGAGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAGACUGU 11475
2376 CAGUCUUG G CUCACUGC 3730 GCAGUGAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAAGACUG 11476
2383 GGCUCACU G CAACUUCU 3731 AGAAGUUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGUGAGCC 11477
2392 CAACUUCU G CCUCUUGG 3732 CCAAGAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAAGUUG 11478
2399 UGCCUCUU G GGUUCAAG 4269 CUUGAACC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAGAGGCA 11479
2400 GCCUCUUG G GUUCAAGU 4270 ACUUGAAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAAGAGGC 11480
2401 CCUCUUGG G UUCAAGUG 3733 CACUUGAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCAAGAGG 11481
2407 GGGUUCAA G UGAUUCUC 3734 GAGAAUCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGAACCC 11482
Figure imgf000238_0001
2409 GUUCAAGU G AUUCUCCU 4271 AGGAGAAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACUUGAAC 11483
2418 AUUCUCCU G CCUCAGCC 3735 GGCUGAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGAGAAU 11484
2424 CUGCCUCA G CCUCCUGA 3736 UCAGGAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGAGGCAG 11485
2431 AGCCUCCU G AGUAGCUG 4272 CAGCUACU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGAGGCU 11486
2433 CCUCCUGA G UAGCUGGA 3737 UCCAGCUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCAGGAGG 11487
2436 CCUGAGUA G CUGGAUUA 3738 UAAUCCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UACUCAGG 11488
2439 GAGUAGCU G GAUUACAG 4273 CUGUAAUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCUACUC 11489
2440 AGUAGCUG G AUUACAGG 4274 CCUGUAAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGCUACU 11490
2447 GGAUUACA G GCAUGUGC 4275 GCACAUGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGUAAUCC 11491
2448 GAUUACAG G CAUGUGCC 3739 GGCACAUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUGUAAUC 11492
2452 ACAGGCAU G UGCCACCC 3740 GGGUGGCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUGCCUGU 11493
2454 AGGCAUGU G CCACCCAC 3741 GUGGGUGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACAUGCCU 11494
2476 UAAUUUUU G UGUUUUUA 3742 UAAAAACA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAAAAUUA 11495
2478 AUUUUUGU G UUUUUAAU 3743 AUUAAAAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACAAAAAU 11496
2490 UUAAUAAA G ACAGGGUU 4276 AACCCUGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUUAUUAA 11497
2494 UAAAGACA G GGUUUCAC 4277 GUGAAACC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGUCUUUA 11498
2495 AAAGACAG G GUUUCACC 4278 GGUGAAAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUGUCUUU 11499
2496 AAGACAGG G UUUCACCA 3744 UGGUGAAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCUGUCUU 11500
2506 UUCACCAU G UUGGCCAG 3745 CUGGCCAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUGGUGAA 11501
2509 ACCAUGUU G GCCAGGCU 4279 AGCCUGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AACAUGGU 11502
2510 CCAUGUUG G CCAGGCUG 3746 CAGCCUGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAACAUGG 11503
2514 GUUGGCCA G GCUGGUCU 4280 AGACCAGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGCCAAC 11504
2515 UUGGCCAG G CUGGUCUC 3747 GAGACCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUGGCCAA 11505
2518 GCCAGGCU G GUCUCAAA 4281 UUUGAGAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCCUGGC 11506
2519 CCAGGCUG G UCUCAAAC 3748 GUUUGAGA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGCCUGG 11507
2532 AAACUCCU G ACCUCAAG 4282 CUUGAGGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGAGUUU 11508
2540 GACCUCAA G UAAUCCAC 3749 GUGGAUUA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUGAGGUC 11509
2551 AUCCACCU G CCUCGGCC 3750 GGCCGAGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGUGGAU 11510
2556 CCUGCCUC G GCCUCCCA 4283 UGGGAGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GAGGCAGG 11511
2557 CUGCCUCG G CCUCCCAA 3751 UUGGGAGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGAGGCAG 11512
2567 CUCCCAAA G UGCUGGGA 3752 UCCCAGCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUUGGGAG 11513
2569 CCCAAAGU G CUGGGAUU 3753 AAUCCCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACUUUGGG 11514
2572 AAAGUGCU G GGAUUACA 4284 UGUAAUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCACUUU 11515
2573 AAGUGCUG G GAUUACAG 4285 CUGUAAUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGCACUU 11516
2574 AGUGCUGG G AUUACAGG 4286 CCUGUAAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCAGCACU 11517
2581 GGAUUACA G GGAUGAGC 4287 GCUCAUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUAAUCC 11518
2582 GAUUACAG G GAUGAGCC 4288 GGCUCAUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGUAAUC 11519
Figure imgf000239_0001
2583 AUUACAGG G AUGAGCCA 4289 UGGCUCAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCUGUAAU 11520
2586 ACAGGGAU G AGCCACCG 4290 CGGUGGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUCCCUGU 11521
2588 AGGGAUGA G CCACCGCG 3754 CGCGGUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCAUCCCU 11522
2594 GAGCCACC G CGCCCAGC 3755 GCUGGGCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGUGGCUC 11523
2596 GCCACCGC G CCCAGCCU 3756 AGGCUGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCGGUGGC 11524
2601 CGCGCCCA G CCUCAUCU 3757 AGAUGAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGGCGCG 11525
2614 AUCUCUUU G UUCUAAAG 3758 CUUUAGAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAAGAGAU 11526
2622 GUUCUAAA G AUGGAAAA 4291 UUUUCCAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUUAGAAC 11527
2625 CUAAAGAU G GAAAAACC 4292 GGUUUUUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUCUUUAG 11528
2626 UAAAGAUG G AAAAACCA 4293 UGGUUUUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAUCUUUA 11529
2664 CUAUUAAU G AAUCAAUC 4294 GAUUGAUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUUAAUAG 11530
2702 UUUCUACC G CUUUUAGG 3759 CCUAAAAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGUAGAAA 11531
2709 CGCUUUUA G GCCAAAAA 4295 UUUUUGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UAAAAGCG 11532
2710 GCUUUUAG G CCAAAAAA 3760 UUUUUUGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUAAAAGC 11533
2721 AAAAAAAU G UAAGAUCG 3761 CGAUCUUA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUUUUUUU 11534
2725 AAAUGUAA G AUCGUUCU 4296 AGAACGAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUACAUUU 11535
2729 GUAAGAUC G UUCUCUGC 3762 GCAGAGAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GAUCUUAC 11536
2736 CGUUCUCU G CCUCACAU 3763 AUGUGAGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGAGAACG 11537
2746 CUCACAUA G CUUACAAG 3764 CUUGUAAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UAUGUGAG 11538
2754 GCUUACAA G CCAGCUGG 3765 CCAGCUGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUGUAAGC 11539
2758 ACAAGCCA G CUGGAGAA 3766 UUCUCCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGCUUGU 11540
2761 AGCCAGCU G GAGAAAUA 4297 UAUUUCUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCUGGCU 11541
2762 GCCAGCUG G AGAAAUAU 4298 AUAUUUCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGCUGGC 11542
2764 CAGCUGGA G AAAUAUGG 4299 CCAUAUUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCAGCUG 11543
2771 AGAAAUAU G GUACUCAU 4300 AUGAGUAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUAUUUCU 11544
2772 GAAAUAUG G UACUCAUU 3767 AAUGAGUA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAUAUUUC 11545
2796 AAAAAAAA G UGAUGUAC 3768 GUACAUCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUUUUUUU 11546
2798 AAAAAAGU G AUGUACAA 4301 UUGUACAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACUUUUUU 11547
Input Sequence = NM_002759. Cut Site = G/ .
Arm Length = 8. Core Sequence = GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG
NM_002759 (Homo sapiens protein kinase, interferon-inducible double stranded RNA dependent (PRKR), mRNA.; 2808 bp)
Figure imgf000240_0001
Table XVIII: Human IKK-gamma and PKR Nucleic Acid and Target molecules
Figure imgf000241_0001
Figure imgf000241_0002
Figure imgf000242_0001
Figure imgf000242_0002
Figure imgf000243_0001
Figure imgf000243_0002
Figure imgf000244_0001
Figure imgf000244_0002
A, G, C, U - Ribo
A, G, C, T (italic) = deoxy lower case = 2 '-O-methyl s = phosphorothioate 3 '-internucleotide linkage
U = 2' -deoxy-2 '-C-allyl uridine
U = 2 '-deoxy-2 '-Amino uridine
C = 2 '-deoxy-2 '-Amino cytidine
I = Inosine
B = inverted deoxyabasic derivative
Figure imgf000245_0001
Table XIX: Human PTGDR Hammerhead and Substrate Sequence
Seq
Pos Substrate ID Hammerhead Seq ID
12 UUCUGGCU A uuuuccuc 4415 GAGGAAAA CUGAUGAGGCCGUUAGGCCGAA AGCCAGAA 11666
14 CUGGCUAU U uuccuccu 4416 AGGAGGAA CUGAUGAGGCCGUUAGGCCGAA AUAGCCAG 11667
Figure imgf000246_0001
15 UGGCUAUU U UCCUCCUG 4417 CAGGAGGA CUGAUGAGGCCGUUAGGCCGAA AAUAGCCA 11668
16 GGCUAUUU U CCUCCUGC 4418 GCAGGAGG CUGAUGAGGCCGUUAGGCCGAA AAAUAGCC 11669
17 GCUAUUUU C CUCCUGCC 4419 GGCAGGAG CUGAUGAGGCCGUUAGGCCGAA AAAAUAGC 11670
20 AUUUUCCU C CUGCCGUU 4420 AACGGCAG CUGAUGAGGCCGUUAGGCCGAA AGGAAAAU 11671
28 CCUGCCGU U CCGACUCG 4421 CGAGUCGG CUGAUGAGGCCGUUAGGCCGAA ACGGCAGG 11672
29 CUGCCGUU C CGACUCGG 4422 CCGAGUCG CUGAUGAGGCCGUUAGGCCGAA AACGGCAG 11673
35 UUCCGACU C GGCACCAG 4423 CUGGUGCC CUGAUGAGGCCGUUAGGCCGAA AGUCGGAA 11674
47 ACCAGAGU C UGUCUCUA 4424 UAGAGACA CUGAUGAGGCCGUUAGGCCGAA ACUCUGGU 11675
51 GAGUCUGU C UCUACUGA 4425 UCAGUAGA CUGAUGAGGCCGUUAGGCCGAA ACAGACUC 11676
53 GUCUGUCU C UACUGAGA 4426 UCUCAGUA CUGAUGAGGCCGUUAGGCCGAA AGACAGAC 11677
55 CUGUCUCU A CUGAGAAC 4427 GUUCUCAG CUGAUGAGGCCGUUAGGCCGAA AGAGACAG 11678
73 CAGCGCGU C AGGGCCGA 4428 UCGGCCCU CUGAUGAGGCCGUUAGGCCGAA ACGCGCUG 11679
85 GCCGAGCU C UUCACUGG 4429 CCAGUGAA CUGAUGAGGCCGUUAGGCCGAA AGCUCGGC 11680
87 CGAGCUCU U CACUGGCC 4430 GGCCAGUG CUGAUGAGGCCGUUAGGCCGAA AGAGCUCG 11681
88 GAGCUCUU C ACUGGCCU 4431 AGGCCAGU CUGAUGAGGCCGUUAGGCCGAA AAGAGCUC 11682
100 GGCCUGCU C CGCGCUCU 4432 AGAGCGCG CUGAUGAGGCCGUUAGGCCGAA AGCAGGCC 11683
107 UCCGCGCU C UUCAAUGC 4433 GCAUUGAA CUGAUGAGGCCGUUAGGCCGAA AGCGCGGA 11684
109 CGCGCUCU u GAAUGCCA 4434 UGGCAUUG CUGAUGAGGCCGUUAGGCCGAA AGAGCGCG 11685
110 GCGCUCUU c AAUGCCAG 4435 CUGGCAUU CUGAUGAGGCCGUUAGGCCGAA AAGAGCGC 11686
130 GAGGCGCU c ACCCUGCA 4436 UGCAGGGU CUGAUGAGGCCGUUAGGCCGAA AGCGCCUG 11687
145 CAGAGCGU c CCGCCUCU 4437 AGAGGCGG CUGAUGAGGCCGUUAGGCCGAA ACGCUCUG 11688
152 UCCCGCCU c UCAAAGAG 4438 CUCUUUGA CUGAUGAGGCCGUUAGGCCGAA AGGCGGGA 11689
154 CCGCCUCU c AAAGAGGG 4439 CCCUCUUU CUGAUGAGGCCGUUAGGCCGAA AGAGGCGG 11690
178 CCGCGAGU u UAGAUAGG 4440 CCUAUCUA CUGAUGAGGCCGUUAGGCCGAA ACUCGCGG 11691
179 CGCGAGUU u AGAUAGGA 4441 UCCUAUCU CUGAUGAGGCCGUUAGGCCGAA AACUCGCG 11692
180 GCGAGUUU A GAUAGGAG 4442 CUCCUAUC CUGAUGAGGCCGUUAGGCCGAA AAACUCGC 11693
184 GUUUAGAU A GGAGGUUC 443 GAACCUCC CUGAUGAGGCCGUUAGGCCGAA AUCUAAAC 11694
191 UAGGAGGU U CCUGCCGU 4444 ACGGCAGG CUGAUGAGGCCGUUAGGCCGAA ACCUCCUA 11695
192 AGGAGGUU C CUGCCGUG 4445 CACGGCAG CUGAUGAGGCCGUUAGGCCGAA AACCUCCU 11696
220 GCCGCCCU C GGAGCUUU 4446 AAAGCUCC CUGAUGAGGCCGUUAGGCCGAA AGGGCGGC 11697
227 UCGGAGCU U UUUCUGUG 4447 CACAGAAA CUGAUGAGGCCGUUAGGCCGAA AGCUCCGA 11698
228 CGGAGCUU U UUCUGUGG 4448 CCAGAGAA CUGAUGAGGCCGUUAGGCCGAA AAGCUCCG 11699
229 GGAGCUUU U UCUGUGGC 4449 GCCACAGA CUGAUGAGGCCGUUAGGCCGAA AAAGCUCC 11700
230 GAGCUUUU U CUGUGGCG 4450 CGCCACAG CUGAUGAGGCCGUUAGGCCGAA AAAAGCUC 11701
231 AGCUUUUU C UGUGGCGC 4451 GCGCCACA CUGAUGAGGCCGUUAGGCCGAA AAAAAGCU 11702
244 GCGCAGCU U CUCCGCCC 4452 GGGCGGAG CUGAUGAGGCCGUUAGGCCGAA AGCUGCGC 11703
245 CGCAGCUU C UCCGCCCG 4453 CGGGCGGA CUGAUGAGGCCGUUAGGCCGAA AAGCUGCG 11704
Figure imgf000247_0001
247 CAGCUUCU C CGCCCGAG 4454 CUCGGGCG CUGAUGAGGCCGUUAGGCCGAA AGAAGCUG 11705
280 CGGGGGCU C CUUAGCAC 4455 GUGCUAAG CUGAUGAGGCCGUUAGGCCGAA AGCCCCCG 11706
283 GGGCUCCU U AGCACCCG 4456 CGGGUGCU CUGAUGAGGCCGUUAGGCCGAA AGGAGCCC 11707
284 GGCUCCUU A GCACCCGG 4457 CCGGGUGC CUGAUGAGGCCGUUAGGCCGAA AAGGAGCC 11708
306 GGGGCCCU C GCCCUUCC 4458 GGAAGGGC CUGAUGAGGCCGUUAGGCCGAA AGGGCCCC 11709
312 CUCGCCCU U CCGCAGCC 4459 GGCUGCGG CUGAUGAGGCCGUUAGGCCGAA AGGGCGAG 11710
313 UCGCCCUU C CGCAGCCU 4460 AGGCUGCG CUGAUGAGGCCGUUAGGCCGAA AAGGGCGA 11711
322 CGCAGCCU u CACUCCAG 4461 CUGGAGUG CUGAUGAGGCCGUUAGGCCGAA AGGCUGCG 11712
323 GCAGCCUU c ACUCCAGC 4462 GCUGGAGU CUGAUGAGGCCGUUAGGCCGAA AAGGCUGC 11713
327 CCUUCACU c CAGCCCUC 4463 GAGGGCUG CUGAUGAGGCCGUUAGGCCGAA AGUGAAGG 11714
335 CCAGCCCU c UGCUCCCG 4464 CGGGAGCA CUGAUGAGGCCGUUAGGCCGAA AGGGCUGG 11715
340 CCUCUGCU c CCGCACGC 4465 GCGUGCGG CUGAUGAGGCCGUUAGGCCGAA AGCAGAGG 11716
357 CAUGAAGU c GCCGUUCU 4466 AGAACGGC CUGAUGAGGCCGUUAGGCCGAA ACUUCAUG 11717
363 GUCGCCGU u CUACCGCU 4467 AGCGGUAG CUGAUGAGGCCGUUAGGCCGAA ACGGCGAC 11718
364 UCGCCGUU c UACCGCUG 4468 CAGCGGUA CUGAUGAGGCCGUUAGGCCGAA AACGGCGA 11719
366 GCCGUUCU A CCGCUGCC 4469 GGCAGCGG CUGAUGAGGCCGUUAGGCCGAA AGAACGGC 11720
387 CACCACCU C UGUGGAAA 4470 UUUCCACA CUGAUGAGGCCGUUAGGCCGAA AGGUGGUG 11721
405 AGGCAACU C GGCGGUGA 4471 UCACCGCC CUGAUGAGGCCGUUAGGCCGAA AGUUGCCU 11722
427 GGGGUGCU c UUCAGCAC 4472 GUGCUGAA CUGAUGAGGCCGUUAGGCCGAA AGGACCCC 11723
429 GGUGCUCU u CAGCACCG 4473 CGGUGCUG CUGAUGAGGCCGUUAGGCCGAA AGAGCACC 11724
430 GUGCUCUU c AGCACCGG 4 7 CCGGUGCU CUGAUGAGGCCGUUAGGCCGAA AAGAGCAC 11725
442 ACCGGCCU c CUGGGCAA 4475 UUGCCCAG CUGAUGAGGCCGUUAGGCCGAA AGGCCGGU 11726
480 GGCGCGCU c GGGGCUGG 4476 CCAGCCCC CUGAUGAGGCCGUUAGGCCGAA AGCGCGCC 11727
498 GUGGUGCU c GCGGCGUC 4477 GACGCCGC CUGAUGAGGCCGUUAGGCCGAA AGCACCAC 11728
506 CGCGGCGU c CACUGCGC 4478 GCGCAGUG CUGAUGAGGCCGUUAGGCCGAA ACGCCGCG 11729
525 GCUGCCCU c GGUCUUCU 4479 AGAAGACC CUGAUGAGGCCGUUAGGCCGAA AGGGCAGC 11730
529 CCCUCGGU c UUCUACAU 4480 AUGUAGAA CUGAUGAGGCCGUUAGGCCGAA ACCGAGGG 11731
531 CUCGGUCU u CUACAUGC 4481 GCAUGUAG CUGAUGAGGCCGUUAGGCCGAA AGACCGAG 11732
532 UCGGUCUU c UACAUGCU 4482 AGCAUGUA CUGAUGAGGCCGUUAGGCCGAA AAGACCGA 11733
534 GGUCUUCU A CAUGCUGG 4483 CCAGCAUG CUGAUGAGGCCGUUAGGCCGAA AGAAGACC 11734
559 CUGACGGU c ACCGACUU 4484 AAGUCGGU CUGAUGAGGCCGUUAGGCCGAA ACCGUCAG 11735
567 CACCGACU U GCUGGGCA 4485 UGCCCAGC CUGAUGAGGCCGUUAGGCCGAA AGUCGGUG 11736
583 AAGUGCCU C CUAAGCCC 4486 GGGCUUAG CUGAUGAGGCCGUUAGGCCGAA AGGCACUU 11737
586 UGCCUCCU A AGCCCGGU 4487 ACCGGGCU CUGAUGAGGCCGUUAGGCCGAA AGGAGGCA 11738
609 GGCUGCCU A CGCUCAGA 4488 UCUGAGCG CUGAUGAGGCCGUUAGGCCGAA AGGCAGCC 11739
614 CCUACGCU C AGAACCGG 4489 CCGGUUCU CUGAUGAGGCCGUUAGGCCGAA AGCGUAGG 11740
626 ACCGGAGU C UGCGGGUG 4490 CACCCGCA CUGAUGAGGCCGUUAGGCCGAA ACUCCGGU 11741
Figure imgf000248_0001
637 CGGGUGCU U GCGCCCGC 4491 GCGGGCGC CUGAUGAGGCCGUUAGGCCGAA AGCACCCG 11742
648 GCCCGCAU U GGACAACU 4 92 AGUUGUCC CUGAUGAGGCCGUUAGGCCGAA AUGCGGGC 11743
657 GGACAACU C GUUGUGCC 93 GGCACAAC CUGAUGAGGCCGUUAGGCCGAA AGUUGUCC 11744
660 CAACUCGU u GUGCCAAG 4494 CUUGGCAC CUGAUGAGGCCGUUAGGCCGAA ACGAGUUG 11745
672 CCAAGCCU u CGCCUUCU 4495 AGAAGGCG CUGAUGAGGCCGUUAGGCCGAA AGGCUUGG 11746
673 CAAGCCUU c GCCUUCUU 4496 AAGAAGGC CUGAUGAGGCCGUUAGGCCGAA AAGGCUUG 11747
678 CUUCGCCU u CUUCAUGU 4497 ACAUGAAG CUGAUGAGGCCGUUAGGCCGAA AGGCGAAG 11748
679 UUCGCCUU c UUCAUGUC 4498 GACAUGAA CUGAUGAGGCCGUUAGGCCGAA AAGGCGAA 11749
681 CGCCUUCU u CAUGUCCU 4499 AGGACAUG CUGAUGAGGCCGUUAGGCCGAA AGAAGGCG 11750
682 GCCUUCUU c AUGUCCUU 4500 AAGGACAU CUGAUGAGGCCGUUAGGCCGAA AAGAAGGC 11751
687 CUUCAUGU c CUUCUUUG 4501 CAAAGAAG CUGAUGAGGCCGUUAGGCCGAA ACAUGAAG 11752
690 CAUGUCCU u CUUUGGGC 4502 GCCCAAAG CUGAUGAGGCCGUUAGGCCGAA AGGACAUG 11753
691 AUGUCCUU c UUUGGGCU 4503 AGCCCAAA CUGAUGAGGCCGUUAGGCCGAA AAGGACAU 11754
693 GUCCUUCU u UGGGCUCU 4504 AGAGCCCA CUGAUGAGGCCGUUAGGCCGAA AGAAGGAC 11755
694 UCCUUCUU u GGGCUCUC 4505 GAGAGCCC CUGAUGAGGCCGUUAGGCCGAA AAGAAGGA 11756
700 UUUGGGCU c UCCUCGAC 4506 GUCGAGGA CUGAUGAGGCCGUUAGGCCGAA AGCCCAAA 11757
702 UGGGCUCU c CUCGACAC 4507 GUGUCGAG CUGAUGAGGCCGUUAGGCCGAA AGAGCCCA 11758
705 GCUCUCCU c GACACUGC 4508 GCAGUGUC CUGAUGAGGCCGUUAGGCCGAA AGGAGAGC 11759
718 CUGCAACU c CUGGCCAU 4509 AUGGCCAG CUGAUGAGGCCGUUAGGCCGAA AGUUGCAG 11760
745 UGCUGGCU c UCCCUAGG 4510 CCUAGGGA CUGAUGAGGCCGUUAGGCCGAA AGCCAGCA 11761
747 CUGGCUCU c CCUAGGGC 4511 GCCCUAGG CUGAUGAGGCCGUUAGGCCGAA AGAGCCAG 11762
751 CUCUCCCU A GGGCACCC 4512 GGGUGCCC CUGAUGAGGCCGUUAGGCCGAA AGGGAGAG 11763
761 GGCACCCU u UCUUCUAC 4513 GUAGAAGA CUGAUGAGGCCGUUAGGCCGAA AGGGUGCC 11764
762 GCACCCUU u CUUCUACC 4514 GGUAGAAG CUGAUGAGGCCGUUAGGCCGAA AAGGGUGC 11765
763 CACCCUUU c UUCUACCG 4515 CGGUAGAA CUGAUGAGGCCGUUAGGCCGAA AAAGGGUG 11766
765 CCCUUUCU u CUACCGAC 4516 GUCGGUAG CUGAUGAGGCCGUUAGGCCGAA AGAAAGGG 11767
766 ccuuucuu c UACCGACG 4517 CGUCGGUA CUGAUGAGGCCGUUAGGCCGAA AAGAAAGG 11768
768 UUUCUUCU A CCGACGGC 4518 GCCGUCGG CUGAUGAGGCCGUUAGGCCGAA AGAAGAAA 11769
781 CGGCACAU c ACCCUGCG 4519 CGCAGGGU CUGAUGAGGCCGUUAGGCCGAA AUGUGCCG 11770
825 GAGCGCCU u CUCCCUGG 4520 CCAGGGAG CUGAUGAGGCCGUUAGGCCGAA AGGCGCUC 11771
826 AGCGCCUU c UCCCUGGC 4521 GCCAGGGA CUGAUGAGGCCGUUAGGCCGAA AAGGCGCU 11772
828 CGCCUUCU C CCUGGCUU 4522 AAGCCAGG CUGAUGAGGCCGUUAGGCCGAA AGAAGGCG 11773
836 CCCUGGCU U UCUGCGCG 4523 CGCGCAGA CUGAUGAGGCCGUUAGGCCGAA AGCCAGGG 11774
837 CCUGGCUU U CUGCGCGC 4524 GCGCGCAG CUGAUGAGGCCGUUAGGCCGAA AAGCCAGG 11775
838 CUGGCUUU C UGCGCGCU 4525 AGCGCGCA CUGAUGAGGCCGUUAGGCCGAA AAAGCCAG 11776
847 UGCGCGCU A CCUUUCAU 4526 AUGAAAGG CUGAUGAGGCCGUUAGGCCGAA AGCGCGCA 11777
851 CGCUACCU U UCAUGGGC 4527 GCCCAUGA CUGAUGAGGCCGUUAGGCCGAA AGGUAGCG 11778
Figure imgf000249_0001
852 GCUACCUU U CAUGGGCU 4528 AGCCCAUG CUGAUGAGGCCGUUAGGCCGAA AAGGUAGC 11779
853 CUACCUUU C AUGGGCUU 4529 AAGCCCAU CUGAUGAGGCCGUUAGGCCGAA AAAGGUAG 11780
861 CAUGGGCU U CGGGAAGU 4530 ACUUCCCG CUGAUGAGGCCGUUAGGCCGAA AGCCCAUG 11781
862 AUGGGCUU C GGGAAGUU 4531 AACUUCCC CUGAUGAGGCCGUUAGGCCGAA AAGCCCAU 11782
870 CGGGAAGU U CGUGCAGU 4532 ACUGCACG CUGAUGAGGCCGUUAGGCCGAA ACUUCCCG 11783
871 GGGAAGUU c GUGCAGUA 4533 UACUGCAC CUGAUGAGGCCGUUAGGCCGAA AACUUCCC 11784
879 CGUGCAGU A CUGCCCCG 4534 CGGGGCAG CUGAUGAGGCCGUUAGGCCGAA ACUGCACG 11785
900 CUGGUGCU U UAUCCAGA 4535 UCUGGAUA CUGAUGAGGCCGUUAGGCCGAA AGCACCAG 11786
901 UGGUGCUU U AUCCAGAU 536 AUCUGGAU CUGAUGAGGCCGUUAGGCCGAA AAGCACCA 11787
902 GGUGCUUU A UCCAGAUG 4537 CAUCUGGA CUGAUGAGGCCGUUAGGCCGAA AAAGCACC 11788
904 UGCUUUAU C CAGAUGGU 4538 ACCAUCUG CUGAUGAGGCCGUUAGGCCGAA AUAAAGCA 11789
913 CAGAUGGU C CACGAGGA 4539 UCCUCGUG CUGAUGAGGCCGUUAGGCCGAA ACCAUCUG 11790
927 GGAGGGCU C GCUGUCGG 4540 CCGACAGC CUGAUGAGGCCGUUAGGCCGAA AGCCCUCC 11791
933 CUCGCUGU C GGUGCUGG 4541 CCAGCACC CUGAUGAGGCCGUUAGGCCGAA ACAGCGAG 11792
945 GCUGGGGU A CUCUGUGC 4542 GCACAGAG CUGAUGAGGCCGUUAGGCCGAA ACCCCAGC 11793
948 GGGGUACU C UGUGCUCU 4543 AGAGCACA CUGAUGAGGCCGUUAGGCCGAA AGUACCCC 11794
955 UCUGUGCU C UACUCCAG 4544 CUGGAGUA CUGAUGAGGCCGUUAGGCCGAA AGCACAGA 11795
957 UGUGCUCU A CUCCAGCC 4545 GGCUGGAG CUGAUGAGGCCGUUAGGCCGAA AGAGCACA 11796
960 GCUCUACU C CAGCCUCA 45 6 UGAGGCUG CUGAUGAGGCCGUUAGGCCGAA AGUAGAGC 11797
967 UCCAGCCU C AUGGCGCU 547 AGCGCCAU CUGAUGAGGCCGUUAGGCCGAA AGGCUGGA 11798
982 CUGCUGGU C CUCGCCAC 4548 GUGGCGAG CUGAUGAGGCCGUUAGGCCGAA ACCAGCAG 11799
985 CUGGUCCU C GCCACCGU 4549 ACGGUGGC CUGAUGAGGCCGUUAGGCCGAA AGGACCAG 11800
1006 UGCAACCU C GGCGCCAU 4550 AUGGCGCC CUGAUGAGGCCGUUAGGCCGAA AGGUUGCA 11801
1024 CGCAACCU C UAUGCGAU 4551 AUCGCAUA CUGAUGAGGCCGUUAGGCCGAA AGGUUGCG 11802
1026 CAACCUCU A UGCGAUGC 4552 GCAUCGCA CUGAUGAGGCCGUUAGGCCGAA AGAGGUUG 11803
1062 CCCGCGCU C CUGCACCA 4553 UGGUGCAG CUGAUGAGGCCGUUAGGCCGAA AGCGCGGG 11804
1110 GGAAGCGU C CCCUCAGC 4554 GCUGAGGG CUGAUGAGGCCGUUAGGCCGAA ACGCUUCC 11805
1115 CGUCCCCU C AGCCCCUG 4555 CAGGGGCU CUGAUGAGGCCGUUAGGCCGAA AGGGGACG 11806
1136 AGCUGGAU C ACCUCCUG 4556 CAGGAGGU CUGAUGAGGCCGUUAGGCCGAA AUCCAGCU 11807
1141 GAUCACCU c CUGCUGCU 4557 AGCAGCAG CUGAUGAGGCCGUUAGGCCGAA AGGUGAUC 11808
1168 ACCGUGCU c UUCACUAU 4558 AUAGUGAA CUGAUGAGGCCGUUAGGCCGAA AGCACGGU 11809
1170 CGUGCUCU U CACUAUGU 4559 ACAUAGUG CUGAUGAGGCCGUUAGGCCGAA AGAGCACG 11810
1171 GUGCUCUU C ACUAUGUG 4560 CACAUAGU CUGAUGAGGCCGUUAGGCCGAA AAGAGCAC 11811
1175 UCUUCACU A UGUGUUCU 4561 AGAACACA CUGAUGAGGCCGUUAGGCCGAA AGUGAAGA 11812
1181 CUAUGUGU U CUCUGCCC 4562 GGGCAGAG CUGAUGAGGCCGUUAGGCCGAA ACAGAUAG 11813
1182 UAUGUGUU C UCUGCCCG 4563 CGGGCAGA CUGAUGAGGCCGUUAGGCCGAA AACACAUA 11814
1184 UGUGUUCU c UGCCCGUA 4564 UACGGGCA CUGAUGAGGCCGUUAGGCCGAA AGAACACA 11815
Figure imgf000250_0001
1192 CUGCCCGU A AUUUAUCG 4565 CGAUAAAU CUGAUGAGGCCGUUAGGCCGAA ACGGGCAG 11816
1195 CCCGUAAU U UAUCGCGC 4566 GCGCGAUA CUGAUGAGGCCGUUAGGCCGAA AUUACGGG 11817
1196 CCGUAAUU U AUCGCGCU 4567 AGCGCGAU CUGAUGAGGCCGUUAGGCCGAA AAUUACGG 11818
1197 CGUAAUUU A UCGCGCUU 4568 AAGCGCGA CUGAUGAGGCCGUUAGGCCGAA AAAUUACG 11819
1199 UAAUUUAU C GCGCUUAC 4569 GUAAGCGC CUGAUGAGGCCGUUAGGCCGAA AUAAAUUA 11820
1205 AUCGCGCU U ACUAUGGA 4570 UCCAUAGU CUGAUGAGGCCGUUAGGCCGAA AGCGCGAU 11821
1206 UCGCGCUU A CUAUGGAG 4571 CUCCAUAG CUGAUGAGGCCGUUAGGCCGAA AAGCGCGA 11822
1209 CGCUUACU A UGGAGCAU 4572 AUGCUCCA CUGAUGAGGCCGUUAGGCCGAA AGUAAGCG 11823
1218 UGGAGCAU U UAAGGAUG 4573 CAUCCUUA CUGAUGAGGCCGUUAGGCCGAA AUGCUCCA 11824
1219 GGAGCAUU U AAGGAUGU 4574 ACAUCCUU CUGAUGAGGCCGUUAGGCCGAA AAUGCUCC 11825
1220 GAGCAUUU A AGGAUGUC 4575 GACAUCCU CUGAUGAGGCCGUUAGGCCGAA AAAUGCUC 11826
1228 AAGGAUGU C AAGGAGAA 4576 UUCUCCUU CUGAUGAGGCCGUUAGGCCGAA ACAUCCUU 11827
1248 CAGGACCU C UGAAGAAG 4577 CUUCUUCA CUGAUGAGGCCGUUAGGCCGAA AGGUCCUG 11828
1267 GAAGACCU C CGAGCCUU 4578 AAGGCUCG CUGAUGAGGCCGUUAGGCCGAA AGGUCUUC 11829
1275 CCGAGCCU U GCGAUUUC 4579 GAAAUCGC CUGAUGAGGCCGUUAGGCCGAA AGGCUCGG 11830
1281 CUUGCGAU U UCUAUCUG 4580 CAGAUAGA CUGAUGAGGCCGUUAGGCCGAA AUCGCAAG 11831
1282 UUGCGAUU U CUAUCUGU 4581 ACAGAUAG CUGAUGAGGCCGUUAGGCCGAA AAUCGCAA 11832
1283 UGCGAUUU C UAUCUGUG 4582 CACAGAUA CUGAUGAGGCCGUUAGGCCGAA AAAUCGCA 11833
1285 CGAUUUCU A UCUGUGAU 4583 AUCACAGA CUGAUGAGGCCGUUAGGCCGAA AGAAAUCG 11834
1287 AUUUCUAU C UGUGAUUU 4584 AAAUCACA CUGAUGAGGCCGUUAGGCCGAA AUAGAAAU 11835
1294 UCUGUGAU U UCAAUUGU 4585 ACAAUUGA CUGAUGAGGCCGUUAGGCCGAA AUCACAGA 11836
1295 CUGUGAUU U CAAUUGUG 4586 CAGAAUUG CUGAUGAGGCCGUUAGGCCGAA AAUCACAG 11837
1296 UGUGAUUU C AAUUGUGG 4587 CCACAAUU CUGAUGAGGCCGUUAGGCCGAA AAAUCACA 11838
1300 AUUUCAAU U GUGGACCC 4588 GGGUCCAC CUGAUGAGGCCGUUAGGCCGAA AUUGAAAU 11839
1310 UGGACCCU U GGAUUUUU 4589 AAAAAUCC CUGAUGAGGCCGUUAGGCCGAA AGGGUCCA 11840
1315 CCUUGGAU U UUUAUCAU 4590 AUGAUAAA CUGAUGAGGCCGUUAGGCCGAA AUCCAAGG 11841
1316 CUUGGAUU u UUAUCAUU 4591 AAUGAUAA CUGAUGAGGCCGUUAGGCCGAA AAUCCAAG 11842
1317 UUGGAUUU u UAUCAUUU 4592 AAAUGAUA CUGAUGAGGCCGUUAGGCCGAA AAAUCCAA 11843
1318 UGGAUUUU u AUCAUUUU 4593 AAAAUGAU CUGAUGAGGCCGUUAGGCCGAA AAAAUCCA 11844
1319 GGAUUUUU A UCAUUUUC 4594 GAAAAUGA CUGAUGAGGCCGUUAGGCCGAA AAAAAUCC 11845
1321 AUUUUUAU C AUUUUCAG 4595 CUGAAAAU CUGAUGAGGCCGUUAGGCCGAA AUAAAAAU 11846
1324 UUUAUCAU U UUCAGAUC 4596 GAUCUGAA CUGAUGAGGCCGUUAGGCCGAA AUGAUAAA 11847
1325 UUAUCAUU U UCAGAUCU 4597 AGAUCUGA CUGAUGAGGCCGUUAGGCCGAA AAUGAUAA 11848
1326 UAUCAUUU U CAGAUCUC 4598 GAGAUCUG CUGAUGAGGCCGUUAGGCCGAA AAAUGAUA 11849
1327 AUCAUUUU C AGAUCUCC 4599 GGAGAUCU CUGAUGAGGCCGUUAGGCCGAA AAAAUGAU 11850
1332 UUUCAGAU C UCCAGUAU 4600 AUACUGGA CUGAUGAGGCCGUUAGGCCGAA AUCUGAAA 11851
1334 UCAGAUCU c CAGUAUUU 4601 AAAUACUG CUGAUGAGGCCGUUAGGCCGAA AGAUCUGA 11852
Figure imgf000251_0001
1339 UCUCCAGU A UUUCGGAU 4602 AUCCGAAA CUGAUGAGGCCGUUAGGCCGAA ACUGGAGA 11853
1341 UCCAGUAU U UCGGAUAU 4603 AUAUCCGA CUGAUGAGGCCGUUAGGCCGAA AUACUGGA 11854
1342 CCAGUAUU U CGGAUAUU 4604 AAUAUCCG CUGAUGAGGCCGUUAGGCCGAA AAUACUGG 11855
1343 CAGUAUUU C GGAUAUUU 4605 AAAUAUCC CUGAUGAGGCCGUUAGGCCGAA AAAUACUG 11856
1348 UUUCGGAU A UUUUUUCA 4606 UGAAAAAA CUGAUGAGGCCGUUAGGCCGAA AUCCGAAA 11857
1350 UCGGAUAU U UUUUCACA 4607 UGUGAAAA CUGAUGAGGCCGUUAGGCCGAA AUAUCCGA 11858
1351 CGGAUAUU U UUUCACAA 4608 UUGUGAAA CUGAUGAGGCCGUUAGGCCGAA AAUAUCCG 11859
1352 GGAUAUUU U UUCACAAG 4609 CUUGUGAA CUGAUGAGGCCGUUAGGCCGAA AAAUAUCC 11860
1353 GAUAUUUU U UCACAAGA 4610 UCUUGUGA CUGAUGAGGCCGUUAGGCCGAA AAAAUAUC 11861
1354 AUAUUUUU U CACAAGAU 4611 AUCUUGUG CUGAUGAGGCCGUUAGGCCGAA AAAAAUAU 11862
1355 UAUUUUUU C ACAAGAUU 4612 AAUCUUGU CUGAUGAGGCCGUUAGGCCGAA AAAAAAUA 11863
1363 CACAAGAU U UUCAUUAG 4613 CUAAUGAA CUGAUGAGGCCGUUAGGCCGAA AUCUUGUG 11864
1364 ACAAGAUU U UCAUUAGA 4614 UCUAAUGA CUGAUGAGGCCGUUAGGCCGAA AAUCUUGU 11865
1365 CAAGAUUU U CAUUAGAC 4615 GUCUAAUG CUGAUGAGGCCGUUAGGCCGAA AAAUCUUG 11866
1366 AAGAUUUU C AUUAGACC 4616 GGUCUAAU CUGAUGAGGCCGUUAGGCCGAA AAAAUCUU 11867
1369 AUUUUCAU U AGACCUCU 4617 AGAGGUCU CUGAUGAGGCCGUUAGGCCGAA AUGAAAAU 11868
1370 UUUUCAUU A GACCUCUU 4618 AAGAGGUC CUGAUGAGGCCGUUAGGCCGAA AAUGAAAA 11869
1376 UUAGACCU C UUAGGUAC 4619 GUACCUAA CUGAUGAGGCCGUUAGGCCGAA AGGUCUAA 11870
1378 AGACCUCU U AGGUACAG 4620 CUGUACCU CUGAUGAGGCCGUUAGGCCGAA AGAGGUCU 11871
1379 GACCUCUU A GGUACAGG 4621 CCUGUACC CUGAUGAGGCCGUUAGGCCGAA AAGAGGUC 11872
1383 UCUUAGGU A CAGGAGCC 4622 GGCUCCUG CUGAUGAGGCCGUUAGGCCGAA ACCUAAGA 11873
1403 GCAGCAAU U CCACUAAC 4623 GUUAGUGG CUGAUGAGGCCGUUAGGCCGAA AUUGCUGC 11874
1404 CAGCAAUU C CACUAACA 4624 UGUUAGUG CUGAUGAGGCCGUUAGGCCGAA AAUUGCUG 11875
1409 AUUCCACU A ACAUGGAA 4625 UUCCAUGU CUGAUGAGGCCGUUAGGCCGAA AGUGGAAU 11876
1419 CAUGGAAU C CAGUCUGU 4626 ACAGACUG CUGAUGAGGCCGUUAGGCCGAA AUUCCAUG 11877
1424 AAUCCAGU C UGUGACAG 4627 CUGUCACA CUGAUGAGGCCGUUAGGCCGAA ACUGGAUU 11878
1436 GACAGUGU u UUUCACUC 628 GAGUGAAA CUGAUGAGGCCGUUAGGCCGAA ACACUGUC 11879
1437 ACAGUGUU u UUCACUCU 4629 AGAGUGAA CUGAUGAGGCCGUUAGGCCGAA AACACUGU 11880
1438 CAGUGUUU u UCACUCUG 4630 CAGAGUGA CUGAUGAGGCCGUUAGGCCGAA AAACACUG 11881
1439 AGUGUUUU u CACUCUGU 4631 ACAGAGUG CUGAUGAGGCCGUUAGGCCGAA AAAACACU 11882
1440 GUGUUUUU c ACUCUGUG 4632 CACAGAGU CUGAUGAGGCCGUUAGGCCGAA AAAAACAC 11883
1444 UUUUCACU C UGUGGUAA 4633 UUACCACA CUGAUGAGGCCGUUAGGCCGAA AGUGAAAA 11884
1451 UCUGUGGU A AGCUGAGG 4634 CCUCAGCU CUGAUGAGGCCGUUAGGCCGAA ACCACAGA 11885
1463 UGAGGAAU A UGUCACAU 4635 AUGUGACA CUGAUGAGGCCGUUAGGCCGAA AUUCCUCA 11886
1467 GAAUAUGU C ACAUUUUC 4636 GAAAAUGU CUGAUGAGGCCGUUAGGCCGAA ACAUAUUC 11887
1472 UGUCACAU U UUCAGUCA 4637 UGACUGAA CUGAUGAGGCCGUUAGGCCGAA AUGUGACA 11888
1473 GUCACAUU U UCAGUCAA 4638 UUGACUGA CUGAUGAGGCCGUUAGGCCGAA AAUGUGAC 11889
Figure imgf000252_0001
1474 UCAGAUUU U CAGUCAAA 4639 UUUGACUG CUGAUGAGGCCGUUAGGCCGAA AAAUGUGA 11890
1475 CACAUUUU C AGUCAAAG 4640 CUUUGACU CUGAUGAGGCCGUUAGGCCGAA AAAAUGUG 11891
1479 UUUUCAGU C AAAGAACC 4641 GGUUCUUU CUGAUGAGGCCGUUAGGCCGAA ACUGAAAA 11892
Input Sequence = PTGDR_composit . Cut Site = UH/ . Arm Length = 8. Core Sequence CUGAUGAG GCCGUUAGGC CGAA
PTGDR_composit (1 to 993 of HSU31332 (PTGDR 51) + 1 to 495 of HSU31099 (PTGDR 31); 1488 nt)
Underlined region can be any X sequence or linker, as described herein.
Table XX: Human PTGDR Inozyme and Substrate Sequence
Figure imgf000253_0001
129 CCAGGCGC U CACCCUGC 4675 GCAGGGUG CUGAUGAGGCCGUUAGGCCGAA ICGCCUGG 11926
131 AGGCGCUC A CCCUGCAG 4676 CUGCAGGG CUGAUGAGGCCGUUAGGCCGAA IAGCGCCU 11927
133 GCGCUCAC C CUGCAGAG 4677 CUCUGCAG CUGAUGAGGCCGUUAGGCCGAA IUGAGCGC 11928
134 CGCUCACC C UGCAGAGC 4678 GCUCUGCA CUGAUGAGGCCGUUAGGCCGAA IGUGAGCG 11929
135 GCUCACCC U GCAGAGCG 4679 CGCUCUGC CUGAUGAGGCCGUUAGGCCGAA IGGUGAGC 11930
138 CACCCUGC A GAGCGUCC 4680 GGACGCUC CUGAUGAGGCCGUUAGGCCGAA ICAGGGUG 11931
Figure imgf000254_0001
146 AGAGCGUC C CGCCUCUC 4681 GAGAGGCG CUGAUGAGGCCGUUAGGCCGAA IACGCUCU 11932
147 GAGCGUCC C GCCUCUCA 4682 UGAGAGGC CUGAUGAGGCCGUUAGGCCGAA IGACGCUC 11933
150 CGUCCCGC C UCUCAAAG 4683 CUUUGAGA CUGAUGAGGCCGUUAGGCCGAA ICGGGACG 11934
151 GUCCCGCC U CUCAAAGA 4684 UCUUUGAG CUGAUGAGGCCGUUAGGCCGAA IGCGGGAC 11935
153 CCCGCCUC u CAAAGAGG 4685 CCUCUUUG CUGAUGAGGCCGUUAGGCCGAA IAGGCGGG 11936
155 CGCCUCUC A AAGAGGGG 4686 CCCCUCUU CUGAUGAGGCCGUUAGGCCGAA IAGAGGCG 11937
170 GGUGUGAC C CGCGAGUU 4687 AACUCGCG CUGAUGAGGCCGUUAGGCCGAA IUCACACC 11938
171 GUGUGACC C GCGAGUUU 4688 AAACUCGC CUGAUGAGGCCGUUAGGCCGAA IGUCACAC 11939
193 GGAGGUUC C UGCCGUGG 4689 CCACGGCA CUGAUGAGGCCGUUAGGCCGAA IAACCUCC 11940
194 GAGGUUCC u GCCGUGGG 4690 CCCACGGC CUGAUGAGGCCGUUAGGCCGAA IGAACCUC 11941
197 GUUCCUGC c GUGGGGAA 4691 UUCCCCAC CUGAUGAGGCCGUUAGGCCGAA ICAGGAAC 11942
207 UGGGGAAC A CCCCGCCG 4692 CGGCGGGG CUGAUGAGGCCGUUAGGCCGAA IUUCCCCA 11943
209 GGGAACAC C CCGCCGCC 4693 GGCGGCGG CUGAUGAGGCCGUUAGGCCGAA IUGUUCCC 11944
210 GGAACACC C CGCCGCCC 4694 GGGCGGCG CUGAUGAGGCCGUUAGGCCGAA IGUGUUCC 11945
211 GAACACCC C GCCGCCCU 4695 AGGGCGGC CUGAUGAGGCCGUUAGGCCGAA IGGUGUUC 11946
214 CACCCCGC C GCCCUCGG 4696 CCGAGGGC CUGAUGAGGCCGUUAGGCCGAA ICGGGGUG 11947
217 CCCGCCGC c CUCGGAGC 4697 GCUCCGAG CUGAUGAGGCCGUUAGGCCGAA ICGGCGGG 11948
218 CCGCCGCC c UCGGAGCU 4698 AGCUCCGA CUGAUGAGGCCGUUAGGCCGAA IGCGGCGG 11949
219 CGCCGCCC u CGGAGCUU 4699 AAGCUCCG CUGAUGAGGCCGUUAGGCCGAA IGGCGGCG 11950
226 CUCGGAGC u UUUUCUGU 4700 ACAGAAAA CUGAUGAGGCCGUUAGGCCGAA ICUCCGAG 11951
232 GCUUUUUC u GUGGCGCA 4701 UGCGCCAC CUGAUGAGGCCGUUAGGCCGAA IAAAAAGC 11952
240 UGUGGCGC A GCUUCUCC 4702 GGAGAAGC CUGAUGAGGCCGUUAGGCCGAA ICGCCACA 11953
243 GGCGCAGC U UCUCCGCC 4703 GGCGGAGA CUGAUGAGGCCGUUAGGCCGAA ICUGCGCC 11954
246 GCAGCUUC U CCGCCCGA 4704 UCGGGCGG CUGAUGAGGCCGUUAGGCCGAA IAAGCUGC 11955
248 AGCUUCUC C GCCCGAGC 4705 GCUCGGGC CUGAUGAGGCCGUUAGGCCGAA lAGAAGCU 11956
251 UUCUCCGC C CGAGCCGC 4706 GCGGCUCG CUGAUGAGGCCGUUAGGCCGAA ICGGAGAA 11957
252 UCUCCGCC C GAGCCGCG 4707 CGCGGCUC CUGAUGAGGCCGUUAGGCCGAA IGCGGAGA 11958
257 GCCCGAGC c GCGCGCGG 4708 CCGCGCGC CUGAUGAGGCCGUUAGGCCGAA ICUCGGGC 11959
269 CGCGGAGC u GCCGGGGG 4709 CCCCCGGC CUGAUGAGGCCGUUAGGCCGAA ICUCCGCG 11960
272 GGAGCUGC c GGGGGCUC 4710 GAGCCCCC CUGAUGAGGCCGUUAGGCCGAA ICAGCUCC 11961
279 CCGGGGGC u CCUUAGCA 4711 UGCUAAGG CUGAUGAGGCCGUUAGGCCGAA ICCCCCGG 11962
281 GGGGGCUC C UUAGCACC 4712 GGUGCUAA CUGAUGAGGCCGUUAGGCCGAA IAGCCCCC 11963
282 GGGGCUCC U UAGCACCC 4713 GGGUGCUA CUGAUGAGGCCGUUAGGCCGAA IGAGCCCC 11964
287 UCCUUAGC A CCCGGGCG 4714 CGCCCGGG CUGAUGAGGCCGUUAGGCCGAA ICUAAGGA 11965
289 CUUAGCAC C CGGGCGCC 4715 GGCGCCCG CUGAUGAGGCCGUUAGGCCGAA IUGCUAAG 11966
290 UUAGCACC C GGGCGCCG 4716 CGGCGCCC CUGAUGAGGCCGUUAGGCCGAA IGUGCUAA 11967
297 CCGGGCGC C GGGGCCCU 4717 AGGGCCCC CUGAUGAGGCCGUUAGGCCGAA ICGCCCGG 11968
Figure imgf000255_0001
303 GCCGGGGC C CUCGCCCU 4718 AGGGCGAG CUGAUGAGGCCGUUAGGCCGAA ICCCCGGC 11969
304 CCGGGGCC c UCGCCCUU 4719 AAGGGCGA CUGAUGAGGCCGUUAGGCCGAA IGCCCCGG 11970
305 CGGGGCCC u CGCCCUUC 4720 GAAGGGCG CUGAUGAGGCCGUUAGGCCGAA IGGCCCCG 11971
309 GCCCUCGC c CUUCCGCA 4721 UGCGGAAG CUGAUGAGGCCGUUAGGCCGAA ICGAGGGC 11972
310 CCCUCGCC c UUCCGCAG 4722 CUGCGGAA CUGAUGAGGCCGUUAGGCCGAA IGCGAGGG 11973
311 CCUCGCCC u UCCGCAGC 4723 GCUGCGGA CUGAUGAGGCCGUUAGGCCGAA IGGCGAGG 11974
314 CGCCCUUC c GCAGCCUU 4724 AAGGCUGC CUGAUGAGGCCGUUAGGCCGAA IAAGGGCG 11975
317 CCUUCCGC A GCCUUCAC 4725 GUGAAGGC CUGAUGAGGCCGUUAGGCCGAA ICGGAAGG 11976
320 UCCGCAGC C UUCACUCC 4726 GGAGUGAA CUGAUGAGGCCGUUAGGCCGAA ICUGCGGA 11977
321 CCGCAGCC U UCACUCCA 4727 UGGAGUGA CUGAUGAGGCCGUUAGGCCGAA IGCUGCGG 11978
324 CAGCCUUC A CUCCAGCC 4728 GGCUGGAG CUGAUGAGGCCGUUAGGCCGAA IAAGGCUG 11979
326 GCCUUCAC U CCAGCCCU 4729 AGGGCUGG CUGAUGAGGCCGUUAGGCCGAA IUGAAGGC 11980
328 CUUCACUC C AGCCCUCU 4730 AGAGGGCU CUGAUGAGGCCGUUAGGCCGAA IAGUGAAG 11981
329 UUCACUCC A GCCCUCUG 4731 CAGAGGGC CUGAUGAGGCCGUUAGGCCGAA IGAGUGAA 11982
332 ACUCCAGC C CUCUGCUC 4732 GAGCAGAG CUGAUGAGGCCGUUAGGCCGAA ICUGGAGU 11983
333 CUCCAGCC C UCUGCUCC 4733 GGAGCAGA CUGAUGAGGCCGUUAGGCCGAA IGCUGGAG 11984
334 UCCAGCCC U CUGCUCCC 4734 GGGAGCAG CUGAUGAGGCCGUUAGGCCGAA IGGCUGGA 11985
336 CAGCCCUC U GCUCCCGC 4735 GCGGGAGC CUGAUGAGGCCGUUAGGCCGAA IAGGGCUG 11986
339 CCCUCUGC U CCCGCACG 4736 CGUGCGGG CUGAUGAGGCCGUUAGGCCGAA ICAGAGGG 11987
341 CUCUGCUC C CGCACGCC 4737 GGCGUGCG CUGAUGAGGCCGUUAGGCCGAA IAGCAGAG 11988
342 UCUGCUCC C GCACGCCA 4738 UGGCGUGC CUGAUGAGGCCGUUAGGCCGAA IGAGCAGA 11989
345 GCUCCCGC A CGCCAUGA 4739 UCAUGGCG CUGAUGAGGCCGUUAGGCCGAA ICGGGAGC 11990
349 CCGCACGC C AUGAAGUC 4740 GACUUCAU CUGAUGAGGCCGUUAGGCCGAA ICGUGCGG 11991
350 CGCACGCC A UGAAGUCG 4741 CGACUUCA CUGAUGAGGCCGUUAGGCCGAA IGCGUGCG 11992
360 GAAGUCGC C GUUCUACC 4742 GGUAGAAC CUGAUGAGGCCGUUAGGCCGAA ICGACUUC 11993
365 CGCCGUUC U ACCGCUGC 4743 GCAGCGGU CUGAUGAGGCCGUUAGGCCGAA IAACGGCG 11994
368 CGUUCUAC C GCUGCCAG 4744 CUGGCAGC CUGAUGAGGCCGUUAGGCCGAA IUAGAACG 11995
371 UCUACCGC U GCCAGAAC 4745 GUUCUGGC CUGAUGAGGCCGUUAGGCCGAA ICGGUAGA 11996
374 ACCGCUGC c AGAACACC 4746 GGUGUUCU CUGAUGAGGCCGUUAGGCCGAA ICAGCGGU 11997
375 CCGCUGCC A GAACACCA 4747 UGGUGUUC CUGAUGAGGCCGUUAGGCCGAA IGCAGCGG 11998
380 GCCAGAAC A CCACCUCU 4748 AGAGGUGG CUGAUGAGGCCGUUAGGCCGAA IUUCUGGC 11999
382 CAGAACAC C ACCUCUGU 4749 ACAGAGGU CUGAUGAGGCCGUUAGGCCGAA IUGUUCUG 12000
383 AGAACACC A CCUCUGUG 4750 CACAGAGG CUGAUGAGGCCGUUAGGCCGAA IGUGUUCU 12001
385 AACACCAC C UCUGUGGA 4751 UCCACAGA CUGAUGAGGCCGUUAGGCCGAA IUGGUGUU 12002
386 ACACCACC U CUGUGGAA 4752 UUCCACAG CUGAUGAGGCCGUUAGGCCGAA IGUGGUGU 12003
388 ACCACCUC U GUGGAAAA 4753 UUUUCCAC CUGAUGAGGCCGUUAGGCCGAA IAGGUGGU 12004
401 AAAAAGGC A ACUCGGCG 4754 CGCCGAGU CUGAUGAGGCCGUUAGGCCGAA ICCUUUUU 12005
Figure imgf000256_0001
404 AAGGCAAC U CGGCGGUG 4755 CACCGCCG CUGAUGAGGCCGUUAGGCCGAA IUUGCCUU 12006
426 CGGGGUGC U CUUCAGCA 4756 UGCUGAAG CUGAUGAGGCCGUUAGGCCGAA ICACCCCG 12007
428 GGGUGCUC U UCAGCACC 4757 GGUGCUGA CUGAUGAGGCCGUUAGGCCGAA IAGCACCC 12008
431 UGCUCUUC A GCACCGGC 4758 GCCGGUGC CUGAUGAGGCCGUUAGGCCGAA IAAGAGCA 12009
434 UCUUCAGC A CCGGCCUC 4759 GAGGCCGG CUGAUGAGGCCGUUAGGCCGAA ICUGAAGA 12010
436 UUCAGCAC C GGCCUCCU 4760 AGGAGGCC CUGAUGAGGCCGUUAGGCCGAA lUGCUGAA 12011
440 GCACCGGC C UCCUGGGC 4761 GCCCAGGA CUGAUGAGGCCGUUAGGCCGAA ICCGGUGC 12012
441 CACCGGCC U CCUGGGCA 4762 UGCCCAGG CUGAUGAGGCCGUUAGGCCGAA IGCCGGUG 12013
443 CCGGCCUC C UGGGCAAC 4763 GUUGCCCA CUGAUGAGGCCGUUAGGCCGAA IAGGCCGG 12014
444 CGGCCUCC U GGGCAACC 4764 GGUUGCCC CUGAUGAGGCCGUUAGGCCGAA IGAGGCCG 12015
449 UCCUGGGC A ACCUGCUG 4765 CAGCAGGU CUGAUGAGGCCGUUAGGCCGAA ICCCAGGA 12016
452 UGGGCAAC C UGCUGGCC 4766 GGCCAGCA CUGAUGAGGCCGUUAGGCCGAA IUUGCCCA 12017
453 GGGCAACC U GCUGGCCC 4767 GGGCCAGC CUGAUGAGGCCGUUAGGCCGAA IGUUGCCC 12018
456 CAACCUGC U GGCCCUGG 4768 CCAGGGCC CUGAUGAGGCCGUUAGGCCGAA ICAGGUUG 12019
460 CUGCUGGC C CUGGGGCU 4769 AGCCCCAG CUGAUGAGGCCGUUAGGCCGAA ICCAGCAG 12020
461 UGCUGGCC C UGGGGCUG 4770 CAGCCCCA CUGAUGAGGCCGUUAGGCCGAA IGCCAGCA 12021
462 GCUGGCCC U GGGGCUGC 4771 GCAGCCCC CUGAUGAGGCCGUUAGGCCGAA IGGCCAGC 12022
468 CCUGGGGC U GCUGGCGC 4772 GCGCCAGC CUGAUGAGGCCGUUAGGCCGAA ICCCCAGG 12023
471 GGGGCUGC U GGCGCGCU 4773 AGCGCGCC CUGAUGAGGCCGUUAGGCCGAA ICAGCCCC 12024
479 UGGCGCGC U CGGGGCUG 4774 CAGCCCCG CUGAUGAGGCCGUUAGGCCGAA ICGCGCCA 12025
486 CUCGGGGC U GGGGUGGU 4775 ACCACCCC CUGAUGAGGCCGUUAGGCCGAA ICCCCGAG 12026
497 GGUGGUGC U CGCGGCGU 4776 ACGCCGCG CUGAUGAGGCCGUUAGGCCGAA ICACCACC 12027
507 GCGGCGUC C ACUGCGCC 4777 GGCGCAGU CUGAUGAGGCCGUUAGGCCGAA IACGCCGC 12028
508 CGGCGUCC A CUGCGCCC 4778 GGGCGCAG CUGAUGAGGCCGUUAGGCCGAA IGACGCCG 12029
510 GCGUCCAC U GCGCCCGC 4779 GCGGGCGC CUGAUGAGGCCGUUAGGCCGAA IUGGACGC 12030
515 CACUGCGC C CGCUGCCC 4780 GGGCAGCG CUGAUGAGGCCGUUAGGCCGAA ICGCAGUG 12031
516 ACUGCGCC C GCUGCCCU 4781 AGGGCAGC CUGAUGAGGCCGUUAGGCCGAA IGCGCAGU 12032
519 GCGCCCGC u GCCCUCGG 4782 CCGAGGGC CUGAUGAGGCCGUUAGGCCGAA ICGGGCGC 12033
522 CCCGCUGC C CUCGGUCU 4783 AGACCGAG CUGAUGAGGCCGUUAGGCCGAA ICAGCGGG 12034
523 CCGCUGCC c UCGGUCUU 4784 AAGACCGA CUGAUGAGGCCGUUAGGCCGAA IGCAGCGG 12035
524 CGCUGCCC u CGGUCUUC 4785 GAAGACCG CUGAUGAGGCCGUUAGGCCGAA IGGCAGCG 12036
530 CCUCGGUC U UCUACAUG 4786 CAUGUAGA CUGAUGAGGCCGUUAGGCCGAA IACCGAGG 12037
533 CGGUCUUC U ACAUGCUG 4787 CAGCAUGU CUGAUGAGGCCGUUAGGCCGAA IAAGACCG 12038
536 UCUUCUAC A UGCUGGUG 4788 CACCAGCA CUGAUGAGGCCGUUAGGCCGAA IUAGAAGA 12039
540 CUACAUGC U GGUGUGUG 4789 CACACACC CUGAUGAGGCCGUUAGGCCGAA ICAUGUAG 12040
551 UGUGUGGC C UGACGGUC 4790 GACCGUCA CUGAUGAGGCCGUUAGGCCGAA ICCACACA 12041
552 GUGUGGCC u GACGGUCA 4791 UGACCGUC CUGAUGAGGCCGUUAGGCCGAA IGCCACAC 12042
Figure imgf000257_0001
560 UGACGGUC A CCGACUUG 4792 CAAGUCGG CUGAUGAGGCCGUUAGGCCGAA IACCGUCA 12043
562 ACGGUCAC C GACUUGCU 4793 AGCAAGUC CUGAUGAGGCCGUUAGGCCGAA IUGACCGU 12044
566 UCACCGAC U UGCUGGGC 4794 GCCGAGCA CUGAUGAGGCCGUUAGGCCGAA IUCGGUGA 12045
570 CGACUUGC U GGGCAAGU 4795 ACUUGCCC CUGAUGAGGCCGUUAGGCCGAA ICAAGUCG 12046
575 UGCUGGGC A AGUGCCUC 4796 GAGGCACU CUGAUGAGGCCGUUAGGCCGAA ICCCAGCA 120 7
581 GCAAGUGC C UCCUAAGC 4797 GCUUAGGA CUGAUGAGGCCGUUAGGCCGAA ICACUUGC 12048
582 CAAGUGCC U CCUAAGCC 4798 GGCUUAGG CUGAUGAGGCCGUUAGGCCGAA IGCACUUG 12049
584 AGUGCCUC C UAAGCCCG 4799 CGGGCUUA CUGAUGAGGCCGUUAGGCCGAA IAGGCACU 12050
585 GUGCCUCC U AAGCCCGG 4800 CCGGGCUU CUGAUGAGGCCGUUAGGCCGAA IGAGGCAC 12051
590 UCCUAAGC C CGGUGGUG 4801 CACCACCG CUGAUGAGGCCGUUAGGCCGAA ICUUAGGA 12052
591 CCUAAGCC C GGUGGUGC 4802 GCACCACC CUGAUGAGGCCGUUAGGCCGAA IGCUUAGG 12053
600 GGUGGUGC U GGCUGCCU 4803 AGGGAGCC CUGAUGAGGCCGUUAGGCCGAA ICACCACC 12054
604 GUGCUGGC U GCCUACGC 4804 GCGUAGGC CUGAUGAGGCCGUUAGGCCGAA ICCAGCAC 12055
607 CUGGCUGC C UACGCUCA 4805 UGAGCGUA CUGAUGAGGCCGUUAGGCCGAA ICAGCCAG 12056
608 UGGCUGCC U ACGCUCAG 4806 CUGAGCGU CUGAUGAGGCCGUUAGGCCGAA IGCAGCCA 12057
613 GCCUACGC u CAGAACCG 4807 CGGUUCUG CUGAUGAGGCCGUUAGGCCGAA ICGUAGGC 12058
615 CUACGCUC A GAACCGGA 4808 UCCGGUUC CUGAUGAGGCCGUUAGGCCGAA IAGCGUAG 12059
620 CUCAGAAC C GGAGUCUG 4809 CAGACUCC CUGAUGAGGCCGUUAGGCCGAA IUUCUGAG 12060
627 CCGGAGUC U GCGGGUGC 4810 GCACCCGC CUGAUGAGGCCGUUAGGCCGAA IACUCCGG 12061
636 GCGGGUGC U UGCGCCCG 4811 CGGGCGCA CUGAUGAGGCCGUUAGGCCGAA ICACCCGC 12062
642 GCUUGCGC C CGCAUUGG 4812 CCAAUGCG CUGAUGAGGCCGUUAGGCCGAA ICGCAAGC 12063
643 CUUGCGCC c GCAUUGGA 4813 UCCAAUGC CUGAUGAGGCCGUUAGGCCGAA IGCGCAAG 12064
646 GCGCCCGC A UUGGACAA 4814 UUGUCCAA CUGAUGAGGCCGUUAGGCCGAA ICGGGCGC 12065
653 CAUUGGAC A ACUCGUUG 4815 CAACGAGU CUGAUGAGGCCGUUAGGCCGAA IUCCAAUG 12066
656 UGGACAAC U CGUUGUGC 4816 GCACAACG CUGAUGAGGCCGUUAGGCCGAA IUUGUCCA 12067
665 CGUUGUGC C AAGCCUUC 4817 GAAGGCUU CUGAUGAGGCCGUUAGGCCGAA ICACAACG 12068
666 GUUGUGCC A AGCCUUCG 4818 CGAAGGCU CUGAUGAGGCCGUUAGGCCGAA IGCACAAC 12069
670 UGCCAAGC C UUCGCCUU 4819 AAGGCGAA CUGAUGAGGCCGUUAGGCCGAA ICUUGGCA 12070
671 GCCAAGCC U UCGCCUUC 4820 GAAGGCGA CUGAUGAGGCCGUUAGGCCGAA IGCUUGGC 12071
676 GCCUUCGC C UUCUUCAU 4821 AUGAAGAA CUGAUGAGGCCGUUAGGCCGAA ICGAAGGC 12072
677 CCUUCGCC U UCUUCAUG 4822 CAUGAAGA CUGAUGAGGCCGUUAGGCCGAA IGCGAAGG 12073
680 UCGCCUUC U UCAUGUCC 4823 GGACAUGA CUGAUGAGGCCGUUAGGCCGAA IAAGGCGA 12074
683 CCUUCUUC A UGUCCUUC 4824 GAAGGACA CUGAUGAGGCCGUUAGGCCGAA IAAGAAGG 12075
688 UUCAUGUC C UUCUUUGG 4825 CCAAAGAA CUGAUGAGGCCGUUAGGCCGAA IACAUGAA 12076
689 UCAUGUCC U UCUUUGGG 4826 CCCAAAGA CUGAUGAGGCCGUUAGGCCGAA IGACAUGA 12077
692 UGUCCUUC U UUGGGCUC 4827 GAGCCCAA CUGAUGAGGCCGUUAGGCCGAA IAAGGACA 12078
699 CUUUGGGC U CUCCUCGA 4828 UCGAGGAG CUGAUGAGGCCGUUAGGCCGAA ICCCAAAG 12079
Figure imgf000258_0001
701 UUGGGCUC U CCUCGACA 4829 UGUCGAGG CUGAUGAGGCCGUUAGGCCGAA IAGCCCAA 12080
703 GGGCUCUC C UCGACACU 4830 AGUGUCGA CUGAUGAGGCCGUUAGGCCGAA IAGAGCCC 12081
704 GGCUCUCC U CGACACUG 4831 CAGUGUCG CUGAUGAGGCCGUUAGGCCGAA IGAGAGCC 12082
709 UCCUCGAC A CUGCAACU 4832 AGUUGCAG CUGAUGAGGCCGUUAGGCCGAA IUCGAGGA 12083
711 CUCGACAC U GCAACUCC 4833 GGAGUUGC CUGAUGAGGCCGUUAGGCCGAA IUGUCGAG 12084
714 GACACUGC A ACUCCUGG 4834 CCAGGAGU CUGAUGAGGCCGUUAGGCCGAA ICAGUGUC 12085 11 ACUGCAAC U CCUGGCCA 4835 UGGCCAGG CUGAUGAGGCCGUUAGGCCGAA IUUGCAGU 12086
719 UGCAACUC C UGGCCAUG 4836 CAUGGCCA CUGAUGAGGCCGUUAGGCCGAA IAGUUGCA 12087
720 GCAACUCC U GGCCAUGG 4837 CCAUGGCC CUGAUGAGGCCGUUAGGCCGAA IGAGUUGC 12088
724 CUCCUGGC C AUGGCACU 4838 AGUGCCAU CUGAUGAGGCCGUUAGGCCGAA ICCAGGAG 12089
725 UCCUGGCC A UGGCACUG 4839 CAGUGCCA CUGAUGAGGCCGUUAGGCCGAA IGCCAGGA 12090
730 GCCAUGGC A CUGGAGUG 4840 CACUCCAG CUGAUGAGGCCGUUAGGCCGAA ICCAUGGC 12091
732 CAUGGCAC U GGAGUGCU 4841 AGCACUCC CUGAUGAGGCCGUUAGGCCGAA IUGCCAUG 12092
740 UGGAGUGC U GGCUCUCC 4842 GGAGAGCC CUGAUGAGGCCGUUAGGCCGAA ICACUCCA 12093
744 GUGCUGGC U CUCCCUAG 4843 CUAGGGAG CUGAUGAGGCCGUUAGGCCGAA ICCAGCAC 12094
746 GCUGGCUC U CCCUAGGG 4844 CCCUAGGG CUGAUGAGGCCGUUAGGCCGAA IAGCCAGC 12095
748 UGGCUCUC C CUAGGGCA 4845 UGCCCUAG CUGAUGAGGCCGUUAGGCCGAA lAGAGCCA 12096
749 GGCUCUCC C UAGGGCAC 4846 GUGCCCUA CUGAUGAGGCCGUUAGGCCGAA IGAGAGCC 12097
750 GCUCUCCC U AGGGCACC 4847 GGUGCCCU CUGAUGAGGCCGUUAGGCCGAA IGGAGAGC 12098
756 CCUAGGGC A CCCUUUCU 4848 AGAAAGGG CUGAUGAGGCCGUUAGGCCGAA ICCCUAGG 12099
758 UAGGGCAC C CUUUCUUC 4849 GAAGAAAG CUGAUGAGGCCGUUAGGCCGAA IUGCCCUA 12100
759 AGGGCACC C UUUCUUCU 4850 AGAAGAAA CUGAUGAGGCCGUUAGGCCGAA IGUGCCCU 12101
760 GGGCACCC U UUCUUCUA 4851 UAGAAGAA CUGAUGAGGCCGUUAGGCCGAA IGGUGCCC 12102
764 ACCCUUUC U UCUACCGA 4852 UCGGUAGA CUGAUGAGGCCGUUAGGCCGAA IAAAGGGU 12103
767 CUUUCUUC U ACCGACGG 4853 CCGUCGGU CUGAUGAGGCCGUUAGGCCGAA IAAGAAAG 12104
770 UCUUCUAC C GACGGCAC 4854 GUGCCGUC CUGAUGAGGCCGUUAGGCCGAA IUAGAAGA 12105
777 CCGACGGC A CAUCACCC 4855 GGGUGAUG CUGAUGAGGCCGUUAGGCCGAA ICCGUCGG 12106
779 GACGGCAC A UCACCCUG 4856 CAGGGUGA CUGAUGAGGCCGUUAGGCCGAA IUGCCGUC 12107
782 GGCACAUC A CCCUGCGC 4857 GCGCAGGG CUGAUGAGGCCGUUAGGCCGAA IAUGUGCC 12108
784 CACAUCAC C CUGCGCCU 4858 AGGCGCAG CUGAUGAGGCCGUUAGGCCGAA IUGAUGUG 12109
785 ACAUCACC C UGCGCCUG 4859 CAGGCGCA CUGAUGAGGCCGUUAGGCCGAA IGUGAUGU 12110
786 CAUCACCC U GCGCCUGG 4860 CCAGGCGC CUGAUGAGGCCGUUAGGCCGAA IGGUGAUG 12111
791 CCCUGCGC C UGGGCGCA 861 UGCGCCCA CUGAUGAGGCCGUUAGGCCGAA ICGCAGGG 12112
792 CCUGCGCC U GGGCGCAC 4862 GUGCGCCC CUGAUGAGGCCGUUAGGCCGAA IGCGCAGG 12113
799 CUGGGCGC A CUGGUGGC 4863 GCCACCAG CUGAUGAGGCCGUUAGGCCGAA ICGCCCAG 12114
801 GGGCGCAC U GGUGGCCC 4864 GGGCCACC CUGAUGAGGCCGUUAGGCCGAA IUGCGCCC 12115
808 CUGGUGGC C CCGGUGGU 4865 ACCACCGG CUGAUGAGGCCGUUAGGCCGAA ICCACCAG 12116
Figure imgf000259_0001
809 UGGUGGCC C CGGUGGUG 4866 CACCACCG CUGAUGAGGCCGUUAGGCCGAA IGCCACCA 12117
810 GGUGGCCC C GGUGGUGA 4867 UCACCACC CUGAUGAGGCCGUUAGGCCGAA IGGCCACC 12118
823 GUGAGCGC C UUCUCCCU 4868 AGGGAGAA CUGAUGAGGCCGUUAGGCCGAA ICGCUCAC 12119
824 UGAGCGCC U UCUCCCUG 4869 CAGGGAGA CUGAUGAGGCCGUUAGGCCGAA IGCGCUCA 12120
827 GCGCCUUC U CCCUGGCU 4870 AGCCAGGG CUGAUGAGGCCGUUAGGCCGAA IAAGGCGC 12121
829 GCCUUCUC C CUGGCUUU 4871 AAAGCCAG CUGAUGAGGCCGUUAGGCCGAA IAGAAGGC 12122
830 CCUUCUCC C UGGCUUUC 4872 GAAAGCCA CUGAUGAGGCCGUUAGGCCGAA IGAGAAGG 12123
831 CUUCUCCC U GGCUUUCU 4873 AGAAAGCC CUGAUGAGGCCGUUAGGCCGAA IGGAGAAG 12124
835 UCCCUGGC U UUCUGCGC 4874 GCGCAGAA CUGAUGAGGCCGUUAGGCCGAA ICCAGGGA 12125
839 UGGCUUUC U GCGCGCUA 4875 UAGCGCGC CUGAUGAGGCCGUUAGGCCGAA lAAAGCCA 12126
846 CUGCGCGC U ACCUUUCA 4876 UGAAAGGU CUGAUGAGGCCGUUAGGCCGAA ICGCGCAG 12127
849 CGCGCUAC C UUUCAUGG 4877 CCAUGAAA CUGAUGAGGCCGUUAGGCCGAA IUAGCGCG 12128
850 GCGCUACC u UUCAUGGG 4878 CCCAUGAA CUGAUGAGGCCGUUAGGCCGAA IGUAGCGC 12129
854 UACCUUUC A UGGGCUUC 4879 GAAGCCCA CUGAUGAGGCCGUUAGGCCGAA IAAAGGUA 12130
860 UCAUGGGC U UCGGGAAG 4880 CUUCCCGA CUGAUGAGGCCGUUAGGCCGAA ICCCAUGA 12131
876 GUUCGUGC A GUACUGCC 4881 GGCAGUAC CUGAUGAGGCCGUUAGGCCGAA ICACGAAC 12132
881 UGCAGUAC U GCCCCGGC 4882 GCCGGGGC CUGAUGAGGCCGUUAGGCCGAA IUACUGCA 12133
884 AGUACUGC C CCGGCACC 4883 GGUGCCGG CUGAUGAGGCCGUUAGGCCGAA ICAGUACU 12134
885 GUACUGCC C CGGCACCU 4884 AGGUGCCG CUGAUGAGGCCGUUAGGCCGAA IGCAGUAC 12135
886 UACUGCCC C GGCACCUG 4885 CAGGUGCC CUGAUGAGGCCGUUAGGCCGAA IGGCAGUA 12136
890 GCCCCGGC A CCUGGUGC 4886 GCACCAGG CUGAUGAGGCCGUUAGGCCGAA ICCGGGGC 12137
892 CCCGGCAC C UGGUGCUU 4887 AAGCACCA CUGAUGAGGCCGUUAGGCCGAA IUGCCGGG 12138
893 CCGGCACC U GGUGCUUU 4888 AAAGCACC CUGAUGAGGCCGUUAGGCCGAA IGUGCCGG 12139
899 CCUGGUGC U UUAUCCAG 4889 CUGGAUAA CUGAUGAGGCCGUUAGGCCGAA ICACCAGG 12140
905 GCUUUAUC C AGAUGGUC 4890 GACCAUCU CUGAUGAGGCCGUUAGGCCGAA IAUAAAGC 12141
906 CUUUAUCC A GAUGGUCC 4891 GGACCAUC CUGAUGAGGCCGUUAGGCCGAA IGAUAAAG 12142
914 AGAUGGUC C ACGAGGAG 4892 CUCCUCGU CUGAUGAGGCCGUUAGGCCGAA IACCAUCU 12143
915 GAUGGUCC A CGAGGAGG 4893 CCUCCUCG CUGAUGAGGCCGUUAGGCCGAA IGACCAUC 12144
926 AGGAGGGC U CGCUGUCG 4894 CGACAGCG CUGAUGAGGCCGUUAGGCCGAA ICCCUCCU 12145
930 GGGCUCGC U GUCGGUGC 4895 GCACCGAC CUGAUGAGGCCGUUAGGCCGAA ICGAGCCC 12146
939 GUCGGUGC U GGGGUACU 4896 AGUACCCC CUGAUGAGGCCGUUAGGCCGAA ICACCGAC 12147
Figure imgf000260_0001
1067 GCUCCUGC A CCAGGGAC 4934 GUCCCUGG CUGAUGAGGCCGUUAGGCCGAA ICAGGAGC 12185
1069 UCCUGCAC C AGGGACUG 4935 CAGUCCCU CUGAUGAGGCCGUUAGGCCGAA IUGCAGGA 12186
1070 CCUGCACC A GGGACUGU 4936 ACAGUCCC CUGAUGAGGCCGUUAGGCCGAA IGUGCAGG 12187
1076 CCAGGGAC U GUGCCGAG 4937 CUCGGCAC CUGAUGAGGCCGUUAGGCCGAA IUCCCUGG 12188
1081 GACUGUGC C GAGCCGCG 4938 CGCGGCUC CUGAUGAGGCCGUUAGGCCGAA ICACAGUC 12189
1086 UGCCGAGC C GCGCGCGG 4939 CCGCGCGC CUGAUGAGGCCGUUAGGCCGAA ICUCGGCA 12190
Figure imgf000261_0001
llll GAAGCGUC C CCUCAGCC 4940 GGCUGAGG CUGAUGAGGCCGUUAGGCCGAA IACGCUUC 12191
1112 AAGCGUCC C CUCAGCCC 4941 GGGCUGAG CUGAUGAGGCCGUUAGGCCGAA IGACGCUU 12192
1113 AGCGUCCC C UCAGCCCC 4942 GGGGCUGA CUGAUGAGGCCGUUAGGCCGAA IGGACGCU 12193
1114 GCGUCCCC U CAGCCCCU 4943 AGGGGCUG CUGAUGAGGCCGUUAGGCCGAA IGGGACGC 12194
1116 GUCCCCUC A GCCCCUGG 4944 CCAGGGGC CUGAUGAGGCCGUUAGGCCGAA IAGGGGAC 12195
1119 CCCUCAGC C CCUGGAGG 4945 CCUCCAGG CUGAUGAGGCCGUUAGGCCGAA ICUGAGGG 12196
1120 CCUCAGCC C CUGGAGGA 4946 UCCUCCAG CUGAUGAGGCCGUUAGGCCGAA IGCUGAGG 12197
1121 CUCAGCCC C UGGAGGAG 4947 CUCCUCCA CUGAUGAGGCCGUUAGGCCGAA IGGCUGAG 12198
1122 UCAGCCCC u GGAGGAGC 4948 GCUCCUCC CUGAUGAGGCCGUUAGGCCGAA IGGGCUGA 12199
1131 GGAGGAGC u GGAUCACC 4949 GGUGAUCC CUGAUGAGGCCGUUAGGCCGAA ICUCCUCC 12200
1137 GCUGGAUC A CCUCCUGC 4950 GCAGGAGG CUGAUGAGGCCGUUAGGCCGAA IAUCCAGC 12201
1139 UGGAUCAC C UCCUGCUG 4951 CAGCAGGA CUGAUGAGGCCGUUAGGCCGAA IUGAUCCA 12202
1140 GGAUCACC U CCUGCUGC 4952 GCAGCAGG CUGAUGAGGCCGUUAGGCCGAA IGUGAUCC 12203
1142 AUCACCUC C UGCUGCUG 4953 CAGCAGCA CUGAUGAGGCCGUUAGGCCGAA IAGGUGAU 12204
1143 UCACCUCC U GCUGCUGG 4954 CCAGCAGC CUGAUGAGGCCGUUAGGCCGAA IGAGGUGA 12205
1146 CCUCCUGC U GCUGGCGC 4955 GCGCCAGC CUGAUGAGGCCGUUAGGCCGAA ICAGGAGG 12206
1149 CCUGCUGC u GGCGCUGA 4956 UCAGCGCC CUGAUGAGGCCGUUAGGCCGAA ICAGCAGG 12207
1155 GCUGGCGC u GAUGACCG 4957 CGGUCAUC CUGAUGAGGCCGUUAGGCCGAA ICGCCAGC 12208
1162 CUGAUGAC c GUGCUCUU 4958 AAGAGCAC CUGAUGAGGCCGUUAGGCCGAA IUCAUCAG 12209
1167 GACCGUGC u CUUCACUA 4959 UAGUGAAG CUGAUGAGGCCGUUAGGCCGAA ICACGGUC 12210
1169 CCGUGCUC u UCACUAUG 4960 CAUAGUGA CUGAUGAGGCCGUUAGGCCGAA IAGCACGG 12211
1172 UGCUCUUC A CUAUGUGU 4961 ACACAUAG CUGAUGAGGCCGUUAGGCCGAA IAAGAGCA 12212
1174 CUCUUCAC U AUGUGUUC 4962 GAACACAU CUGAUGAGGCCGUUAGGCCGAA IUGAAGAG 12213
1183 AUGUGUUC U CUGCCCGU 4963 ACGGGCAG CUGAUGAGGCCGUUAGGCCGAA lAACACAU 12214
1185 GUGUUCUC U GCCCGUAA 4964 UUACGGGC CUGAUGAGGCCGUUAGGCCGAA IAGAACAC 12215
1188 UUCUCUGC c CGUAAUUU 4965 AAAUUACG CUGAUGAGGCCGUUAGGCCGAA ICAGAGAA 12216
1189 UCUCUGCC c GUAAUUUA 4966 UAAAUUAC CUGAUGAGGCCGUUAGGCCGAA IGCAGAGA 12217
1204 UAUCGCGC u UACUAUGG 4967 CCAUAGUA CUGAUGAGGCCGUUAGGCCGAA ICGCGAUA 12218
1208 GCGCUUAC u AUGGAGCA 4968 UGCUCCAU CUGAUGAGGCCGUUAGGCCGAA IUAAGCGC 12219
1216 UAUGGAGC A UUUAAGGA 4969 UCCUUAAA CUGAUGAGGCCGUUAGGCCGAA ICUCCAUA 12220
1229 AGGAUGUC A AGGAGAAA 4970 UUUCUCCU CUGAUGAGGCCGUUAGGCCGAA IACAUCCU 12221
1241 AGAAAAAC A GGACCUCU 4971 AGAGGUCC CUGAUGAGGCCGUUAGGCCGAA IUUUUUCU 12222
1246 AACAGGAC C UCUGAAGA 4972 UCUUCAGA CUGAUGAGGCCGUUAGGCCGAA IUCCUGUU 12223
1247 ACAGGACC U CUGAAGAA 4973 UUCUUCAG CUGAUGAGGCCGUUAGGCCGAA IGUCCUGU 12224
1249 AGGACCUC U GAAGAAGC 4974 GCUUCUUC CUGAUGAGGCCGUUAGGCCGAA IAGGUCCU 12225
1258 GAAGAAGC A GAAGACCU 4975 AGGUCUUC CUGAUGAGGCCGUUAGGCCGAA ICUUCUUC 12226
1265 CAGAAGAC C UCCGAGCC 4976 GGCUCGGA CUGAUGAGGCCGUUAGGCCGAA IUCUUCUG 12227
Figure imgf000262_0001
1266 AGAAGACC U CCGAGCCU 4977 AGGCUCGG CUGAUGAGGCCGUUAGGCCGAA IGUCUUCU 12228
1268 AAGACCUC C GAGCCUUG 4978 GAAGGCUC CUGAUGAGGCCGUUAGGCCGAA IAGGUCUU 12229
1273 CUCCGAGC C UUGCGAUU 4979 AAUCGCAA CUGAUGAGGCCGUUAGGCCGAA ICUCGGAG 12230
1274 UCCGAGCC U UGCGAUUU 4980 AAAUCGCA CUGAUGAGGCCGUUAGGCCGAA IGCUCGGA 12231
1284 GCGAUUUC U AUCUGUGA 4981 UCACAGAU CUGAUGAGGCCGUUAGGCCGAA IAAAUCGC 12232
1288 UUUCUAUC U GUGAUUUC 4982 GAAAUCAC CUGAUGAGGCCGUUAGGCCGAA IAUAGAAA 12233
1297 GUGAUUUC A AUUGUGGA 4983 UCCACAAU CUGAUGAGGCCGUUAGGCCGAA IAAAUCAC 12234
1307 UUGUGGAC C CUUGGAUU 4984 AAUCCAAG CUGAUGAGGCCGUUAGGCCGAA IUCCACAA 12235
1308 UGUGGACC C UUGGAUUU 4985 AAAUCCAA CUGAUGAGGCCGUUAGGCCGAA IGUCCACA 12236
1309 GUGGACCC U UGGAUUUU 4986 AAAAUCCA CUGAUGAGGCCGUUAGGCCGAA IGGUCCAC 12237
1322 UUUUUAUC A UUUUCAGA 4987 UCUGAAAA CUGAUGAGGCCGUUAGGCCGAA IAUAAAAA 12238
1328 UCAUUUUC A GAUCUCCA 4988 UGGAGAUC CUGAUGAGGCCGUUAGGCCGAA IAAAAUGA 12239
1333 UUCAGAUC U CCAGUAUU 4989 AAUACUGG CUGAUGAGGCCGUUAGGCCGAA IAUCUGAA 12240
1335 CAGAUCUC C AGUAUUUC 4990 GAAAUACU CUGAUGAGGCCGUUAGGCCGAA IAGAUCUG 12241
1336 AGAUCUCC A GUAUUUCG 4991 CGAAAUAC CUGAUGAGGCCGUUAGGCCGAA IGAGAUCU 12242
1356 AUUUUUUC A CAAGAUUU 4992 AAAUCUUG CUGAUGAGGCCGUUAGGCCGAA IAAAAAAU 12243
1358 UUUUUCAC A AGAUUUUC 4993 GAAAAUCU CUGAUGAGGCCGUUAGGCCGAA IUGAAAAA 12244
1367 AGAUUUUC A UUAGACCU 4994 AGGUCUAA CUGAUGAGGCCGUUAGGCCGAA IAAAAUCU 12245
1374 CAUUAGAC C UCUUAGGU 4995 ACCUAAGA CUGAUGAGGCCGUUAGGCCGAA IUCUAAUG 12246
1375 AUUAGACC U CUUAGGUA 4996 UACCUAAG CUGAUGAGGCCGUUAGGCCGAA IGUCUAAU 12247
1377 UAGACCUC U UAGGUACA 4997 UGUACCUA CUGAUGAGGCCGUUAGGCCGAA lAGGUCUA 12248
1385 UUAGGUAC A GGAGCCGG 4998 CCGGCUCC CUGAUGAGGCCGUUAGGCCGAA IUACCUAA 12249
1391 ACAGGAGC C GGUGCAGC 4999 GCUGCACC CUGAUGAGGCCGUUAGGCCGAA ICUCCUGU 12250
1397 GCCGGUGC A GCAAUUCC 5000 GGAAUUGC CUGAUGAGGCCGUUAGGCCGAA ICACCGGC 12251
1400 GGUGCAGC A AUUCCACU 5001 AGUGGAAU CUGAUGAGGCCGUUAGGCCGAA ICUGCACC 12252
1405 AGCAAUUC C ACUAACAU 5002 AUGUUAGU CUGAUGAGGCCGUUAGGCCGAA IAAUUGCU 12253
1406 GCAAUUCC A CUAACAUG 5003 CAUGUUAG CUGAUGAGGCCGUUAGGCCGAA IGAAUUGC 12254
1408 AAUUCCAC U AACAUGGA 5004 UCCAUGUU CUGAUGAGGCCGUUAGGCCGAA IUGGAAUU 12255
1412 CCACUAAC A UGGAAUCC 5005 GGAUUCCA CUGAUGAGGCCGUUAGGCCGAA IUUAGUGG 12256
1420 AUGGAAUC C AGUCUGUG 5006 CACAGACU CUGAUGAGGCCGUUAGGCCGAA IAUUCCAU 12257
1421 UGGAAUCC A GUCUGUGA 5007 UCACAGAC CUGAUGAGGCCGUUAGGCCGAA IGAUUCCA 12258
1425 AUCCAGUC U GUGACAGU 5008 ACUGUCAC CUGAUGAGGCCGUUAGGCCGAA IACUGGAU 12259
1431 UCUGUGAC A GUGUUUUU 5009 AAAAACAC CUGAUGAGGCCGUUAGGCCGAA IUCACAGA 12260
1441 UGUUUUUC A CUCUGUGG 5010 CCACAGAG CUGAUGAGGCCGUUAGGCCGAA IAAAAACA 12261
1443 UUUUUCAC U CUGUGGUA 5011 UACCACAG CUGAUGAGGCCGUUAGGCCGAA IUGAAAAA 12262
1445 UUUCACUC U GUGGUAAG 5012 CUUACCAC CUGAUGAGGCCGUUAGGCCGAA IAGUGAAA 12263
1455 UGGUAAGC U GAGGAAUA 5013 UAUUCCUC CUGAUGAGGCCGUUAGGCCGAA ICUUACCA 12264
Figure imgf000263_0001
1468 AAUAUGUC A CAUUUUCA 5014 UGAAAAUG CUGAUGAGGCCGUUAGGCCGAA IACAUAUU 12265
1470 UAUGUCAC A UUUUCAGU 5015 ACUGAAAA CUGAUGAGGCCGUUAGGCCGAA IUGACAUA 12266
1476 ACAUUUUC A GUCAAAGA 5016 UCUUUGAC CUGAUGAGGCCGUUAGGCCGAA IAAAAUGU 12267
1480 UUUCAGUC A AAGAACCA 5017 UGGUUCUU CUGAUGAGGCCGUUAGGCCGAA IACUGAAA 12268
Input Sequence = PTGDR_composit . Cut Site = CH/ .
Arm Length = 8. Core Sequence = CUGAUGAG GCCGUUAGGC CGAA
PTGDR_composit (1 to 993 of HSU31332 (PTGDR 5') + 1 to 495 of HSU31099 (PTGDR 3'); 1488 nt)
Underlined region can be any X sequence or linker, as described herein. I = Inosine
Table XXI: Human PTGDR Zinzyme and Substrate Sequence
Figure imgf000264_0001
215 ACCCCGCC G CCCUCGGA 5051 UCCGAGGG GCCGAAAGGCGAGUGAGGUCU GGCGGGGU 12302
224 CCCUCGGA G CUUUUUCU 5052 AGAAAAAG GCCGAAAGGCGAGUGAGGUCU UCCGAGGG 12303
233 CUUUUUCU G UGGCGCAG 5053 CUGCGCCA GCCGAAAGGCGAGUGAGGUCU AGAAAAAG 12304
236 UUUCUGUG G CGCAGCUU 5054 AAGCUGCG GCCGAAAGGCGAGUGAGGUCU CACAGAAA 12305
238 UCUGUGGC G CAGCUUCU 5055 AGAAGCUG GCCGAAAGGCGAGUGAGGUCU GCCACAGA 12306
241 GUGGCGCA G CUUCUCCG 5056 CGGAGAAG GCCGAAAGGCGAGUGAGGUCU UGCGCCAC 12307
Figure imgf000265_0001
249 GCUUCUCC G CCCGAGCC 5057 GGCUCGGG GCCGAAAGGCGAGUGAGGUCU GGAGAAGC 12308
255 CCGCCCGA G CCGCGCGC 5058 GCGCGCGG GCCGAAAGGCGAGUGAGGUCU UCGGGCGG 12309
258 CCCGAGCC G CGCGCGGA 5059 UCCGCGCG GCCGAAAGGCGAGUGAGGUCU GGCUCGGG 12310
260 CGAGCCGC G CGCGGAGC 5060 GCUCCGCG GCCGAAAGGCGAGUGAGGUCU GCGGCUCG 12311
262 AGCCGCGC G CGGAGCUG 5061 CAGCUCCG GCCGAAAGGCGAGUGAGGUCU GCGCGGCU 12312
267 CGCGCGGA G CUGCCGGG 5062 CCCGGCAG GCCGAAAGGCGAGUGAGGUCU UCCGCGCG 12313
270 GCGGAGCU G CCGGGGGC 5063 GCCCCCGG GCCGAAAGGCGAGUGAGGUCU AGCUCCGC 12314
277 UGCCGGGG G CUCCUUAG 5064 CUAAGGAG GCCGAAAGGCGAGUGAGGUCU CCCCGGCA 12315
285 GCUCCUUA G CACCCGGG 5065 CCCGGGUG GCCGAAAGGCGAGUGAGGUCU UAAGGAGC 12316
293 GCACCCGG G CGCCGGGG 5066 CCCCGGCG GCCGAAAGGCGAGUGAGGUCU CCGGGUGC 12317
295 ACCCGGGC G CCGGGGCC 5067 GGCCCCGG GCCGAAAGGCGAGUGAGGUCU GCCCGGGU 12318
301 GCGCCGGG G CCCUCGCC 5068 GGCGAGGG GCCGAAAGGCGAGUGAGGUCU CCCGGCGC 12319
307 GGGCCCUC G CCCUUCCG 5069 CGGAAGGG GCCGAAAGGCGAGUGAGGUCU GAGGGCCC 12320
315 GCCCUUCC G CAGCCUUC 5070 GAAGGCUG GCCGAAAGGCGAGUGAGGUCU GGAAGGGC 12321
318 CUUCCGCA G CCUUCACU 5071 AGUGAAGG GCCGAAAGGCGAGUGAGGUCU UGCGGAAG 12322
330 UCACUCCA G CCCUCUGC 5072 GCAGAGGG GCCGAAAGGCGAGUGAGGUCU UGGAGUGA 12323
337 AGCCCUCU G CUCCCGCA 5073 UGCGGGAG GCCGAAAGGCGAGUGAGGUCU AGAGGGCU 12324
343 CUGCUCCC G CACGCCAU 5074 AUGGCGUG GCCGAAAGGCGAGUGAGGUCU GGGAGCAG 12325
347 UCCCGCAC G CCAUGAAG 5075 CUUCAUGG GCCGAAAGGCGAGUGAGGUCU GUGCGGGA 12326
355 GCCAUGAA G UCGCCGUU 5076 AACGGCGA GCCGAAAGGCGAGUGAGGUCU UUCAUGGC 12327
358 AUGAAGUC G CCGUUCUA 5077 UAGAACGG GCCGAAAGGCGAGUGAGGUCU GACUUCAU 12328
361 AAGUCGCC G UUCUACCG 5078 CGGUAGAA GCCGAAAGGCGAGUGAGGUCU GGCGACUU 12329
369 GUUCUACC G CUGCCAGA 5079 UCUGGCAG GCCGAAAGGCGAGUGAGGUCU GGUAGAAC 12330
372 CUACCGCU G CCAGAACA 5080 UGUUCUGG GCCGAAAGGCGAGUGAGGUCU AGCGGUAG 12331
389 CCACCUCU G UGGAAAAA 5081 UUUUUCCA GCCGAAAGGCGAGUGAGGUCU AGAGGUGG 12332
399 GGAAAAAG G CAACUCGG 5082 CCGAGUUG GCCGAAAGGCGAGUGAGGUCU CUUUUUCC 12333
407 GCAACUCG G CGGUGAUG 5083 CAUCACCG GCCGAAAGGCGAGUGAGGUCU CGAGUUGC 12334
410 ACUCGGCG G UGAUGGGC 5084 GCCCAUCA GCCGAAAGGCGAGUGAGGUCU CGCCGAGU 12335
417 GGUGAUGG G CGGGGUGC 5085 GCACCCCG GCCGAAAGGCGAGUGAGGUCU CCAUCACC 12336
422 UGGGCGGG G UGCUCUUC 5086 GAAGAGCA GCCGAAAGGCGAGUGAGGUCU CCCGCCCA 12337
424 GGCGGGGU G CUCUUCAG 5087 CUGAAGAG GCCGAAAGGCGAGUGAGGUCU ACCCCGCC 12338
432 GCUCUUCA G CACCGGCC 5088 GGCCGGUG GCCGAAAGGCGAGUGAGGUCU UGAAGAGC 12339
438 CAGCACCG G CCUCCUGG 5089 CCAGGAGG GCCGAAAGGCGAGUGAGGUCU CGGUGCUG 12340
447 CCUCCUGG G CAACCUGC 5090 GCAGGUUG GCCGAAAGGCGAGUGAGGUCU CCAGGAGG 12341
454 GGCAACCU G CUGGCCCU 5091 AGGGCCAG GCCGAAAGGCGAGUGAGGUCU AGGUUGCC 12342
458 ACCUGCUG G CCCUGGGG 5092 CCCCAGGG GCCGAAAGGCGAGUGAGGUCU CAGCAGGU 12343
466 GCCCUGGG G CUGCUGGC 5093 GCCAGCAG GCCGAAAGGCGAGUGAGGUCU CCCAGGGC 12344
Figure imgf000266_0001
469 CUGGGGCU G CUGGCGCG 5094 CGCGCCAG GCCGAAAGGCGAGUGAGGUCU AGCCCCAG 12345
473 GGCUGCUG G CGCGCUCG 5095 CGAGCGCG GCCGAAAGGCGAGUGAGGUCU CAGCAGCC 12346
475 CUGCUGGC G CGCUCGGG 5096 CCCGAGCG GCCGAAAGGCGAGUGAGGUCU GCCAGCAG 12347
477 GCUGGCGC G CUCGGGGC 5097 GCCCCGAG GCCGAAAGGCGAGUGAGGUCU GCGCCAGC 12348
484 CGCUCGGG G CUGGGGUG 5098 CACCCCAG GCCGAAAGGCGAGUGAGGUCU CCCGAGCG 12349
490 GGGCUGGG G UGGUGCUC 5099 GAGCACCA GCCGAAAGGCGAGUGAGGUCU CCCAGCCC 12350
493 CUGGGGUG G UGCUCGCG 5100 CGCGAGCA GCCGAAAGGCGAGUGAGGUCU CACCCCAG 12351
495 GGGGUGGU G CUCGCGGC 5101 GCCGCGAG GCCGAAAGGCGAGUGAGGUCU ACCACCCC 12352
499 UGGUGCUC G CGGCGUCC 5102 GGACGCCG GCCGAAAGGCGAGUGAGGUCU GAGCACCA 12353
502 UGCUCGCG G CGUCCACU 5103 AGUGGACG GCCGAAAGGCGAGUGAGGUCU CGCGAGCA 12354
504 CUCGCGGC G UCCACUGC 5104 GCAGUGGA GCCGAAAGGCGAGUGAGGUCU GCCGCGAG 12355
511 CGUCCACU G CGCCCGCU 5105 AGCGGGCG GCCGAAAGGCGAGUGAGGUCU AGUGGACG 12356
513 UCCACUGC G CCCGCUGC 5106 GCAGCGGG GCCGAAAGGCGAGUGAGGUCU GCAGUGGA 12357
517 CUGCGCCC G CUGCCCUC 5107 GAGGGCAG GCCGAAAGGCGAGUGAGGUCU GGGCGCAG 12358
520 CGCCCGCU G CCCUCGGU 5108 ACCGAGGG GCCGAAAGGCGAGUGAGGUCU AGCGGGCG 12359
527 UGCCCUCG G UCUUCUAC 5109 GUAGAAGA GCCGAAAGGCGAGUGAGGUCU CGAGGGCA 12360
538 UUCUACAU G CUGGUGUG 5110 CACACCAG GCCGAAAGGCGAGUGAGGUCU AUGUAGAA 12361
542 ACAUGCUG G UGUGUGGC 5111 GCCACACA GCCGAAAGGCGAGUGAGGUCU CAGCAUGU 12362
544 AUGCUGGU G UGUGGCCU 5112 AGGCCACA GCCGAAAGGCGAGUGAGGUCU ACCAGCAU 12363
546 GCUGGUGU G UGGCCUGA 5113 UCAGGCCA GCCGAAAGGCGAGUGAGGUCU ACACCAGC 12364
549 GGUGUGUG G CCUGACGG 5114 CCGUCAGG GCCGAAAGGCGAGUGAGGUCU CACACACC 12365
557 GCCUGACG G UCACCGAC 5115 GUCGGUGA GCCGAAAGGCGAGUGAGGUCU CGUCAGGC 12366
568 ACCGACUU G CUGGGCAA 5116 UUGCCCAG GCCGAAAGGCGAGUGAGGUCU AAGUCGGU 12367
573 CUUGCUGG G CAAGUGCC 5117 GGCACUUG GCCGAAAGGCGAGUGAGGUCU CCAGCAAG 12368
577 CUGGGCAA G UGCCUCCU 5118 AGGAGGCA GCCGAAAGGCGAGUGAGGUCU UUGCCCAG 12369
579 GGGGAAGU G CCUCCUAA 5119 UUAGGAGG GCCGAAAGGCGAGUGAGGUCU ACUUGCCC 12370
588 CCUCCUAA G CCCGGUGG 5120 CCACCGGG GCCGAAAGGCGAGUGAGGUCU UUAGGAGG 12371
593 UAAGCCCG G UGGUGCUG 5121 CAGCACCA GCCGAAAGGCGAGUGAGGUCU CGGGCUUA 12372
596 GCCCGGUG G UGCUGGCU 5122 AGCCAGCA GCCGAAAGGCGAGUGAGGUCU CACCGGGC 12373
598 CCGGUGGU G CUGGCUGC 5123 GCAGCCAG GCCGAAAGGCGAGUGAGGUCU ACCACCGG 12374
602 UGGUGCUG G CUGCCUAC 5124 GUAGGCAG GCCGAAAGGCGAGUGAGGUCU CAGCACCA 12375
605 UGCUGGCU G CCUACGCU 5125 AGCGUAGG GCCGAAAGGCGAGUGAGGUCU AGCCAGCA 12376
611 CUGCCUAC G CUCAGAAC 5126 GUUCUGAG GCCGAAAGGCGAGUGAGGUCU GUAGGCAG 12377
624 GAACCGGA G UCUGCGGG 5127 CCCGCAGA GCCGAAAGGCGAGUGAGGUCU UCCGGUUC 12378
628 CGGAGUCU G CGGGUGCU 5128 AGCACCCG GCCGAAAGGCGAGUGAGGUCU AGACUCCG 12379
632 GUCUGCGG G UGCUUGCG 5129 CGCAAGCA GCCGAAAGGCGAGUGAGGUCU CCGCAGAC 12380
634 CUGCGGGU G CUUGCGCC 5130 GGCGCAAG GCCGAAAGGCGAGUGAGGUCU ACCCGCAG 12381
Figure imgf000267_0001
638 GGGUGCUU G CGCCCGCA 5131 UGCGGGCG GCCGAAAGGCGAGUGAGGUCU AAGCACCC 12382
640 GUGCUUGC G CCCGCAUU 5132 AAUGCGGG GCCGAAAGGCGAGUGAGGUCU GCAAGCAC 12383
644 UUGCGCCC G CAUUGGAC 5133 GUCCAAUG GCCGAAAGGCGAGUGAGGUCU GGGCGCAA 12384
658 GACAACUC G UUGUGCCA 5134 UGGCACAA GCCGAAAGGCGAGUGAGGUCU GAGUUGUC 12385
661 AACUCGUU G UGCCAAGC 5135 GCUUGGCA GCCGAAAGGCGAGUGAGGUCU AACGAGUU 12386
663 CUCGUUGU G CCAAGCCU 5136 AGGCUUGG GCCGAAAGGCGAGUGAGGUCU ACAACGAG 12387
668 UGUGCCAA G CCUUCGCC 5137 GGCGAAGG GCCGAAAGGCGAGUGAGGUCU UUGGCACA 12388
674 AAGCCUUC G CCUUCUUC 5138 GAAGAAGG GCCGAAAGGCGAGUGAGGUCU GAAGGCUU 12389
685 UUCUUCAU G UCCUUCUU 5139 AAGAAGGA GCCGAAAGGCGAGUGAGGUCU AUGAAGAA 12390
697 UUCUUUGG G CUCUCCUC 5140 GAGGAGAG GCCGAAAGGCGAGUGAGGUCU CCAAAGAA 12391
712 UCGACACU G CAACUCCU 5141 AGGAGUUG GCCGAAAGGCGAGUGAGGUCU AGUGUCGA 12392
722 AACUCCUG G CCAUGGCA 5142 UGCCAUGG GCCGAAAGGCGAGUGAGGUCU CAGGAGUU 12393
728 UGGCCAUG G CACUGGAG 5143 CUCCAGUG GCCGAAAGGCGAGUGAGGUCU CAUGGCCA 12394
736 GCACUGGA G UGCUGGCU 5144 AGCCAGCA GCCGAAAGGCGAGUGAGGUCU UCCAGUGC 12395
738 ACUGGAGU G CUGGCUCU 5145 AGAGCCAG GCCGAAAGGCGAGUGAGGUCU ACUCCAGU 12396
742 GAGUGCUG G CUCUCCCU 5146 AGGGAGAG GCCGAAAGGCGAGUGAGGUCU CAGCACUC 12397
754 UCCCUAGG G CACCCUUU 5147 AAAGGGUG GCCGAAAGGCGAGUGAGGUCU CCUAGGGA 12398
775 UACCGACG G CACAUCAC 5148 GUGAUGUG GCCGAAAGGCGAGUGAGGUCU CGUCGGUA 12399
787 AUCACCCU G CGCCUGGG 5149 CCCAGGCG GCCGAAAGGCGAGUGAGGUCU AGGGUGAU 12400
789 CACCCUGC G CCUGGGCG 5150 CGCCCAGG GCCGAAAGGCGAGUGAGGUCU GCAGGGUG 12401
795 GCGCCUGG G CGCACUGG 5151 CCAGUGCG GCCGAAAGGCGAGUGAGGUCU CCAGGCGC 12402
797 GCCUGGGC G CACUGGUG 5152 CACCAGUG GCCGAAAGGCGAGUGAGGUCU GCCCAGGC 12403
803 GCGCACUG G UGGCCCCG 5153 CGGGGCCA GCCGAAAGGCGAGUGAGGUCU CAGUGCGC 12404
806 CACUGGUG G CCCCGGUG 5154 CACCGGGG GCCGAAAGGCGAGUGAGGUCU CACCAGUG 12405
812 UGGCCCCG G UGGUGAGC 5155 GCUCACCA GCCGAAAGGCGAGUGAGGUCU CGGGGCCA 12406
815 CCCCGGUG G UGAGCGCC 5156 GGCGCUCA GCCGAAAGGCGAGUGAGGUCU CACCGGGG 12407
819 GGUGGUGA G CGCCUUCU 5157 AGAAGGCG GCCGAAAGGCGAGUGAGGUCU UCACCACC 12408
821 UGGUGAGC G CCUUCUCC 5158 GGAGAAGG GCCGAAAGGCGAGUGAGGUCU GCUCACCA 12409
833 UCUCCCUG G CUUUCUGC 5159 GCAGAAAG GCCGAAAGGCGAGUGAGGUCU CAGGGAGA 12410
840 GGCUUUCU G CGCGCUAC 5160 GUAGCGCG GCCGAAAGGCGAGUGAGGUCU AGAAAGCC 12411
842 CUUUCUGC G CGCUACCU 5161 AGGUAGCG GCCGAAAGGCGAGUGAGGUCU GCAGAAAG 12412
844 UUCUGCGC G CUACCUUU 5162 AAAGGUAG GCCGAAAGGCGAGUGAGGUCU GCGCAGAA 12413
858 UUUCAUGG G CUUCGGGA 5163 UCCCGAAG GCCGAAAGGCGAGUGAGGUCU CCAUGAAA 12414
868 UUCGGGAA G UUCGUGCA 5164 UGCACGAA GCCGAAAGGCGAGUGAGGUCU UUCCCGAA 12415
872 GGAAGUUC G UGCAGUAC 5165 GUACUGGA GCCGAAAGGCGAGUGAGGUCU GAACUUCC 12416
874 AAGUUCGU G CAGUACUG 5166 CAGUACUG GCCGAAAGGCGAGUGAGGUCU ACGAACUU 12417
877 UUCGUGCA G UACUGCCC 5167 GGGCAGUA GCCGAAAGGCGAGUGAGGUCU UGCACGAA 12418
Figure imgf000268_0001
882 GCAGUACU G CCCCGGCA 5168 UGCCGGGG GCCGAAAGGCGAGUGAGGUCU AGUACUGC 12419
888 CUGCCCCG G CACCUGGU 5169 ACCAGGUG GCCGAAAGGCGAGUGAGGUCU CGGGGCAG 12420
895 GGCACCUG G UGCUUUAU 5170 AUAAAGCA GCCGAAAGGCGAGUGAGGUCU CAGGUGCC 12421
897 CACCUGGU G CUUUAUCC 5171 GGAUAAAG GCCGAAAGGCGAGUGAGGUCU ACCAGGUG 12422
911 UCCAGAUG G UCCACGAG 5172 CUCGUGGA GCCGAAAGGCGAGUGAGGUCU CAUCUGGA 12423
924 CGAGGAGG G CUCGCUGU 5173 ACAGCGAG GCCGAAAGGCGAGUGAGGUCU CCUCCUCG 12424
928 GAGGGCUC G CUGUCGGU 5174 ACCGACAG GCCGAAAGGCGAGUGAGGUCU GAGCCCUC 12425
931 GGCUCGCU G UCGGUGCU 5175 AGCACCGA GCCGAAAGGCGAGUGAGGUCU AGCGAGCC 12426
935 CGCUGUCG G UGCUGGGG 5176 CCCCAGCA GCCGAAAGGCGAGUGAGGUCU CGACAGCG 12427
937 CUGUCGGU G CUGGGGUA 5177 UACCCCAG GCCGAAAGGCGAGUGAGGUCU ACCGACAG 12428
943 GUGCUGGG G UACUCUGU 5178 ACAGAGUA GCCGAAAGGCGAGUGAGGUCU CCCAGCAC 12429
950 GGUACUCU G UGCUCUAC 5179 GUAGAGCA GCCGAAAGGCGAGUGAGGUCU AGAGUACC 12430
952 UACUCUGU G CUCUACUC 5180 GAGUAGAG GCCGAAAGGCGAGUGAGGUCU ACAGAGUA 12431
963 CUACUCCA G CCUCAUGG 5181 CCAUGAGG GCCGAAAGGCGAGUGAGGUCU UGGAGUAG 12432
971 GCCUCAUG G CGCUGCUG 5182 CAGCAGCG GCCGAAAGGCGAGUGAGGUCU CAUGAGGC 12433
973 CUCAUGGC G CUGCUGGU 5183 ACCAGCAG GCCGAAAGGCGAGUGAGGUCU GCCAUGAG 12434
976 AUGGCGCU G CUGGUCCU 5184 AGGACCAG GCCGAAAGGCGAGUGAGGUCU AGCGCCAU 12435
980 CGCUGCUG G UCCUCGCC 5185 GGCGAGGA GCCGAAAGGCGAGUGAGGUCU CAGCAGCG 12436
986 UGGUCCUC G CCACCGUG 5186 CACGGUGG GCCGAAAGGCGAGUGAGGUCU GAGGACCA 12437
992 UCGCCACC G UGCUGUGC 5187 GCACAGCA GCCGAAAGGCGAGUGAGGUCU GGUGGCGA 12438
994 GCCACCGU G CUGUGCAA 5188 UUGCACAG GCCGAAAGGCGAGUGAGGUCU ACGGUGGC 12439
997 ACCGUGCU G UGCAACCU 5189 AGGUUGCA GCCGAAAGGCGAGUGAGGUCU AGCACGGU 12440
999 CGUGCUGU G CAACCUCG 5190 CGAGGUUG GCCGAAAGGCGAGUGAGGUCU ACAGCACG 12441
1008 CAACCUCG G CGCCAUGC 5191 GCAUGGCG GCCGAAAGGCGAGUGAGGUCU CGAGGUUG 12442
1010 ACCUCGGC G CCAUGCGC 5192 GCGCAUGG GCCGAAAGGCGAGUGAGGUCU GCCGAGGU 12443
1015 GGCGCCAU G CGCAACCU 5193 AGGUUGCG GCCGAAAGGCGAGUGAGGUCU AUGGCGCC 12444
1017 CGCCAUGC G CAACCUCU 5194 AGAGGUUG GCCGAAAGGCGAGUGAGGUCU GCAUGGCG 12445
1028 ACCUCUAU G CGAUGCAC 5195 GUGCAUCG GCCGAAAGGCGAGUGAGGUCU AUAGAGGU 12446
1033 UAUGCGAU G CACCGGCG 5196 CGCCGGUG GCCGAAAGGCGAGUGAGGUCU AUCGCAUA 12447
1039 AUGCACCG G CGGCUGCA 5197 UGCAGCCG GCCGAAAGGCGAGUGAGGUCU CGGUGCAU 12448
1042 CACCGGCG G CUGCAGCG 5198 CGCUGCAG GCCGAAAGGCGAGUGAGGUCU CGCCGGUG 12449
1045 CGGCGGCU G CAGCGGCA 5199 UGCCGCUG GCCGAAAGGCGAGUGAGGUCU AGCCGCCG 12450
1048 CGGCUGCA G CGGCACCC 5200 GGGUGCCG GCCGAAAGGCGAGUGAGGUCU UGCAGCCG 12451
1051 CUGCAGCG G CACCCGCG 5201 CGCGGGUG GCCGAAAGGCGAGUGAGGUCU CGCUGCAG 12452
1057 CGGCACCC G CGCUCCUG 5202 CAGGAGCG GCCGAAAGGCGAGUGAGGUCU GGGUGCCG 12453
1059 GCACCCGC G CUCCUGCA 5203 UGCAGGAG GCCGAAAGGCGAGUGAGGUCU GCGGGUGC 12454
1065 GCGCUCCU G CACCAGGG 5204 CCCUGGUG GCCGAAAGGCGAGUGAGGUCU AGGAGCGC 12455
Figure imgf000269_0001
1077 CAGGGACU G UGCCGAGC 5205 GCUCGGCA GCCGAAAGGCGAGUGAGGUCU AGUCCCUG 12456
1079 GGGACUGU G CCGAGCCG 5206 CGGCUCGG GCCGAAAGGCGAGUGAGGUCU ACAGUCCC 12457
1084 UGUGCCGA G CCGCGCGC 5207 GCGCGCGG GCCGAAAGGCGAGUGAGGUCU UCGGCACA 12458
1087 GCCGAGCC G CGCGCGGA 5208 UCCGCGCG GCCGAAAGGCGAGUGAGGUCU GGCUCGGC 12459
1089 CGAGCCGC G CGCGGACG 5209 CGUCCGCG GCCGAAAGGCGAGUGAGGUCU GCGGCUCG 12460
1091 AGCCGCGC G CGGACGGG 5210 CCCGUCCG GCCGAAAGGCGAGUGAGGUCU GCGCGGCU 12461
1106 GGAGGGAA G CGUCCCCU 5211 AGGGGACG GCCGAAAGGCGAGUGAGGUCU UUCCCUCC 12462
1108 AGGGAAGC G UCCCCUCA 5212 UGAGGGGA GCCGAAAGGCGAGUGAGGUCU GCUUCCCU 12463
1117 UCCCCUCA G CCCCUGGA 5213 UCCAGGGG GCCGAAAGGCGAGUGAGGUCU UGAGGGGA 12464
1129 CUGGAGGA G CUGGAUCA 5214 UGAUCCAG GCCGAAAGGCGAGUGAGGUCU UCCUCCAG 12465
1144 CACCUCCU G CUGCUGGC 5215 GCCAGCAG GCCGAAAGGCGAGUGAGGUCU AGGAGGUG 12466
1147 CUCCUGCU G CUGGCGCU 5216 AGCGCCAG GCCGAAAGGCGAGUGAGGUCU AGCAGGAG 12467
1151 UGCUGCUG G CGCUGAUG 5217 CAUCAGCG GCCGAAAGGCGAGUGAGGUCU CAGCAGCA 12468
1153 CUGCUGGC G CUGAUGAC 5218 GUCAUCAG GCCGAAAGGCGAGUGAGGUCU GCCAGCAG 12469
1163 UGAUGACC G UGCUCUUC 5219 GAAGAGCA GCCGAAAGGCGAGUGAGGUCU GGUCAUCA 12470
1165 AUGACCGU G CUCUUCAC 5220 GUGAAGAG GCCGAAAGGCGAGUGAGGUCU ACGGUCAU 12471
1177 UUCACUAU G UGUUCUCU 5221 AGAGAACA GCCGAAAGGCGAGUGAGGUCU AUAGUGAA 12472
1179 CACUAUGU G UUCUCUGC 5222 GCAGAGAA GCCGAAAGGCGAGUGAGGUCU ACAUAGUG 12473
1186 UGUUCUCU G CCCGUAAU 5223 AUUACGGG GCCGAAAGGCGAGUGAGGUCU AGAGAACA 12474
1190 CUCUGCCC G UAAUUUAU 5224 AUAAAUUA GCCGAAAGGCGAGUGAGGUCU GGGCAGAG 12475
1200 AAUUUAUC G CGCUUACU 5225 AGUAAGCG GCCGAAAGGCGAGUGAGGUCU GAUAAAUU 12476
1202 UUUAUCGC G CUUACUAU 5226 AUAGUAAG GCCGAAAGGCGAGUGAGGUCU GCGAUAAA 12477
1214 ACUAUGGA G CAUUUAAG 5227 CUUAAAUG GCCGAAAGGCGAGUGAGGUCU UCCAUAGU 12478
1226 UUAAGGAU G UCAAGGAG 5228 CUCCUUGA GCCGAAAGGCGAGUGAGGUCU AUCCUUAA 12479
1256 CUGAAGAA G CAGAAGAC 5229 GUCUUCUG GCCGAAAGGCGAGUGAGGUCU UUCUUCAG 12480
1271 ACCUCCGA G CCUUGCGA 5230 UCGCAAGG GCCGAAAGGCGAGUGAGGUCU UCGGAGGU 12481
1276 CGAGCCUU G CGAUUUCU 5231 AGAAAUCG GCCGAAAGGCGAGUGAGGUCU AAGGCUCG 12482
1289 UUCUAUCU G UGAUUUCA 5232 UGAAAUCA GCCGAAAGGCGAGUGAGGUCU AGAUAGAA 12483
1301 UUUCAAUU G UGGACCCU 5233 AGGGUCCA GCCGAAAGGCGAGUGAGGUCU AAUUGAAA 12484
1337 GAUCUCCA G UAUUUCGG 5234 CCGAAAUA GCCGAAAGGCGAGUGAGGUCU UGGAGAUC 12485
1381 CCUCUUAG G UACAGGAG 5235 CUCCUGUA GCCGAAAGGCGAGUGAGGUCU CUAAGAGG 12486
1389 GUACAGGA G CCGGUGCA 5236 UGCACCGG GCCGAAAGGCGAGUGAGGUCU UCCUGUAC 12487
1393 AGGAGCCG G UGCAGGAA 5237 UUGCUGCA GCCGAAAGGCGAGUGAGGUCU CGGCUCCU 12488
1395 GAGCCGGU G CAGCAAUU 5238 AAUUGCUG GCCGAAAGGCGAGUGAGGUCU ACCGGCUC 12489
1398 CCGGUGCA G CAAUUCCA 5239 UGGAAUUG GCCGAAAGGCGAGUGAGGUCU UGCACCGG 12490
1422 GGAAUCCA G UCUGUGAC 5240 GUCACAGA GCCGAAAGGCGAGUGAGGUCU UGGAUUCC 12491
1426 UCCAGUCU G UGACAGUG 5241 CACUGUCA GCCGAAAGGCGAGUGAGGUCU AGACUGGA 12492
Figure imgf000270_0001
1432 CUGUGACA G UGUUUUUC 5242 GAAAAACA GCCGAAAGGCGAGUGAGGUCU UGUCACAG 12493
1434 GUGACAGU G UUUUUCAC 5243 GUGAAAAA GCCGAAAGGCGAGUGAGGUCU ACUGUCAC 12494
1446 UUCACUCU G UGGUAAGC 5244 GCUUACCA GCCGAAAGGCGAGUGAGGUCU AGAGUGAA 12495
1449 ACUCUGUG G UAAGCUGA 5245 UCAGCUUA GCCGAAAGGCGAGUGAGGUCU CACAGAGU 12496
1453 UGUGGUAA G CUGAGGAA 5246 UUCCUCAG GCCGAAAGGCGAGUGAGGUCU UUACCACA 12497
1465 AGGAAUAU G UCACAUUU 5247 AAAUGUGA GCCGAAAGGCGAGUGAGGUCU AUAUUCCU 12498
1477 CAUUUUCA G UCAAAGAA 5248 UUCUUUGA GCCGAAAGGCGAGUGAGGUCU UGAAAAUG 12499
Input Sequence = PTGDR_composit . Cut Site = G/Y Arm Length = 8. Core Sequence = GCcgaaagGCGaGuCaaGGuCu PTGDR_composit (1 to 993 of HSU31332 (PTGDR 5') + 1 to 495 of HSU31099 (PTGDR 3'); 1488 nt)
Table XXII: Human PTGDR DNAzyme and Substrate Sequence
Seq
Pos Substrate ID DNAzyme Seq ID
9 GAAUUCUG G CUAUUUUC 5018 GAAAATAG GGCTAGCTACAACGA CAGAATTC 12500
12 UUCUGGCU A UUUUCCUC 4415 GAGGAAAA GGCTAGCTACAACGA AGCCAGAA 12501
Figure imgf000271_0001
23 UUCCUCCU G CCGUUCCG 5019 CGGAACGG GGCTAGCTACAACGA AGGAGGAA 12502
26 CUCCUGCC G UUCCGACU 5020 AGTCGGAA GGCTAGCTACAACGA GGCAGGAG 12503
32 CCGUUCCG A CUCGGCAC 5249 GTGCCGAG GGCTAGCTACAACGA CGGAACGG 12504
37 CCGACUCG G CACCAGAG 5021 CTCTGGTG GGCTAGCTACAACGA CGAGTCGG 12505
39 GACUCGGC A CCAGAGUC 4650 GACTCTGG GGCTAGCTACAACGA GCCGAGTC 12506
45 GCACCAGA G UCUGUCUC 5022 GAGACAGA GGCTAGCTACAACGA TCTGGTGC 12507
49 CAGAGUCU G UCUCUACU 5023 AGTAGAGA GGCTAGCTACAACGA AGACTCTG 12508
55 CUGUCUCU A CUGAGAAC 4427 GTTCTCAG GGCTAGCTACAACGA AGAGACAG 12509
62 UACUGAGA A CGCAGCGC 5250 GCGCTGCG GGCTAGCTACAACGA TCTCAGTA 12510
64 CUGAGAAC G CAGCGCGU 5024 ACGCGCTG GGCTAGCTACAACGA GTTCTCAG 12511
67 AGAACGCA G CGCGUCAG 5025 CTGACGCG GGCTAGCTACAACGA TGCGTTCT 12512
69 AACGCAGC G CGUCAGGG 5026 CCCTGACG GGCTAGCTACAACGA GCTGCGTT 12513
71 CGCAGCGC G UCAGGGCC 5027 GGCCCTGA GGCTAGCTACAACGA GCGCTGCG 12514
77 GCGUCAGG G CCGAGCUC 5028 GAGCTCGG GGCTAGCTACAACGA CCTGACGC 12515
82 AGGGCCGA G CUCUUCAC 5029 GTGAAGAG GGCTAGCTACAACGA TCGGCCCT 12516
89 AGCUCUUC A CUGGCCUG 4662 CAGGCCAG GGCTAGCTACAACGA GAAGAGCT 12517
93 CUUCACUG G CCUGCUCC 5030 GGAGCAGG GGCTAGCTACAACGA CAGTGAAG 12518
97 ACUGGCCU G CUCCGCGC 5031 GCGCGGAG GGCTAGCTACAACGA AGGCCAGT 12519
102 CCUGCUCC G CGCUCUUC 5032 GAAGAGCG GGCTAGCTACAACGA GGAGCAGG 12520
104 UGCUCCGC G CUCUUCAA 5033 TTGAAGAG GGCTAGCTACAACGA GCGGAGCA 12521
112 GCUCUUCA A UGCCAGCG 5251 CGCTGGCA GGCTAGCTACAACGA TGAAGAGC 12522
114 UCUUCAAU G CCAGCGCC 5034 GGCGCTGG GGCTAGCTACAACGA ATTGAAGA 12523
118 CAAUGCCA G CGCCAGGC 5035 GCCTGGCG GGCTAGCTACAACGA TGGCATTG 12524
120 AUGCCAGC G CCAGGCGC 5036 GCGCCTGG GGCTAGCTACAACGA GCTGGCAT 12525
125 AGCGCCAG G CGCUCACC 5037 GGTGAGCG GGCTAGCTACAACGA CTGGCGCT 12526
127 CGCCAGGC G CUCACCCU 5038 AGGGTGAG GGCTAGCTACAACGA GCCTGGCG 12527
131 AGGCGCUC A CCCUGCAG 4676 CTGCAGGG GGCTAGCTACAACGA GAGCGCCT 12528
136 CUCACCCU G CAGAGCGU 5039 ACGCTCTG GGCTAGCTACAACGA AGGGTGAG 12529
141 CCUGGAGA G CGUCCCGC 5040 GCGGGACG GGCTAGCTACAACGA TCTGCAGG 12530
143 UGCAGAGC G UCCCGCCU 5041 AGGCGGGA GGCTAGCTACAACGA GCTCTGCA 12531
148 AGCGUCCC G CCUCUCAA 5042 TTGAGAGG GGCTAGCTACAACGA GGGACGCT 12532
163 AAAGAGGG G UGUGACCC 5043 GGGTCACA GGCTAGCTACAACGA CCCTCTTT 12533
165 AGAGGGGU G UGACCCGC 5044 GCGGGTCA GGCTAGCTACAACGA ACCCCTCT 12534
168 GGGGUGUG A CCCGCGAG 5252 CTCGCGGG GGCTAGCTACAACGA CACACCCC 12535
172 UGUGACCC G CGAGUUUA 5045 TAAACTCG GGCTAGCTACAACGA GGGTCACA 12536
176 ACCCGCGA G UUUAGAUA 5046 TATCTAAA GGCTAGCTACAACGA TCGCGGGT 12537
182 GAGUUUAG A UAGGAGGU 5253 ACCTCCTA GGCTAGCTACAACGA CTAAACTC 12538
Figure imgf000272_0001
189 GAUAGGAG G UUCCUGCC 5047 GGCAGGAA GGCTAGCTACAACGA CTCCTATC 12539
195 AGGUUCCU G CCGUGGGG 5048 CCCCACGG GGCTAGCTACAACGA AGGAACCT 12540
198 UUCCUGCC G UGGGGAAC 5049 GTTCCCCA GGCTAGCTACAACGA GGCAGGAA 12541
205 CGUGGGGA A CACCCCGC 5254 GCGGGGTG GGCTAGCTACAACGA TCCCCACG 12542
207 UGGGGAAC A CCCCGCCG 4692 CGGCGGGG GGCTAGCTACAACGA GTTCCCCA 12543
212 AACACCCC G CCGCCCUC 5050 GAGGGCGG GGCTAGCTACAACGA GGGGTGTT 12544
215 ACCCCGCC G CCCUCGGA 5051 TCCGAGGG GGCTAGCTACAACGA GGCGGGGT 12545
224 CCCUCGGA G CUUUUUCU 5052 AGAAAAAG GGCTAGCTACAACGA TCCGAGGG 12546
233 CUUUUUCU G UGGCGCAG 5053 CTGCGCCA GGCTAGCTACAACGA AGAAAAAG 12547
236 UUUCUGUG G CGCAGCUU 5054 AAGCTGCG GGCTAGCTACAACGA CACAGAAA 12548
238 UCUGUGGC G CAGCUUCU 5055 AGAAGCTG GGCTAGCTACAACGA GCCACAGA 12549
241 GUGGCGCA G CUUCUCCG 5056 CGGAGAAG GGCTAGCTACAACGA TGCGCCAC 12550
249 GCUUCUCC G CCCGAGCC 5057 GGCTCGGG GGCTAGCTACAACGA GGAGAAGC 12551
255 CCGCCCGA G CCGCGCGC 5058 GCGCGCGG GGCTAGCTACAACGA TCGGGCGG 12552
258 CCCGAGCC G CGCGCGGA 5059 TCCGCGCG GGCTAGCTACAACGA GGCTCGGG 12553
260 CGAGCCGC G CGCGGAGC 5060 GCTCCGCG GGCTAGCTACAACGA GCGGCTCG 12554
262 AGCCGCGC G CGGAGCUG 5061 CAGCTCCG GGCTAGCTACAACGA GCGCGGCT 12555
267 CGCGCGGA G CUGCCGGG 5062 CCCGGCAG GGCTAGCTACAACGA TCCGCGCG 12556
270 GCGGAGCU G CCGGGGGC 5063 GCCCCCGG GGCTAGCTACAACGA AGCTCCGC 12557
277 UGCCGGGG G CUCCUUAG 5064 CTAAGGAG GGCTAGCTACAACGA CCCCGGCA 12558
285 GCUCCUUA G CACCCGGG 5065 CCCGGGTG GGCTAGCTACAACGA TAAGGAGC 12559
287 UCCUUAGC A CCCGGGCG 4714 CGCCCGGG GGCTAGCTACAACGA GCTAAGGA 12560
293 GCACCCGG G CGCCGGGG 5066 CCCCGGCG GGCTAGCTACAACGA CCGGGTGC 12561
295 ACCCGGGC G CCGGGGCC 5067 GGCCCCGG GGCTAGCTACAACGA GCCCGGGT 12562
301 GCGCCGGG G CCCUCGCC 5068 GGCGAGGG GGCTAGCTACAACGA CCCGGCGC 12563
307 GGGCCCUC G CCCUUCCG 5069 CGGAAGGG GGCTAGCTACAACGA GAGGGCCC 12564
315 GCCCUUCC G CAGCCUUC 5070 GAAGGCTG GGCTAGCTACAACGA GGAAGGGC 12565
318 CUUCCGCA G CCUUGACU 5071 AGTGAAGG GGCTAGCTACAACGA TGCGGAAG 12566
324 CAGCCUUC A CUCCAGCC 4728 GGCTGGAG GGCTAGCTACAACGA GAAGGCTG 12567
330 UCACUCCA G CCCUCUGC 5072 GCAGAGGG GGCTAGCTACAACGA TGGAGTGA 12568
337 AGCCCUCU G CUCCCGCA 5073 TGCGGGAG GGCTAGCTACAACGA AGAGGGCT 12569
343 CUGCUCCC G CACGCCAU 5074 ATGGCGTG GGCTAGCTACAACGA GGGAGCAG 12570
345 GCUCCCGC A CGCCAUGA 4739 TCATGGCG GGCTAGCTACAACGA GCGGGAGC 12571
347 UCCCGCAC G CCAUGAAG 5075 CTTCATGG GGCTAGCTACAACGA GTGCGGGA 12572
350 CGCACGCC A UGAAGUCG 4741 CGACTTCA GGCTAGCTACAACGA GGCGTGCG 12573
355 GCCAUGAA G UCGCCGUU 5076 AACGGCGA GGCTAGCTACAACGA TTCATGGC 12574
358 AUGAAGUC G CCGUUCUA 5077 TAGAACGG GGCTAGCTACAACGA GACTTCAT 12575
Figure imgf000273_0001
361 AAGUCGCC G UUCUACCG 5078 CGGTAGAA GGCTAGCTACAACGA GGCGACTT 12576
366 GCCGUUCU A CCGCUGCC 4469 GGCAGCGG GGCTAGCTACAACGA AGAACGGC 12577
369 GUUCUACC G CUGCCAGA 5079 TCTGGCAG GGCTAGCTACAACGA GGTAGAAC 12578
372 CUACCGCU G CCAGAACA 5080 TGTTCTGG GGCTAGCTACAACGA AGCGGTAG 12579
378 CUGCCAGA A CACCACCU 5255 AGGTGGTG GGCTAGCTACAACGA TCTGGCAG 12580
380 GCCAGAAC A CCACCUCU 4748 AGAGGTGG GGCTAGCTACAACGA GTTCTGGC 12581
383 AGAACACC A CCUCUGUG 4750 CACAGAGG GGCTAGCTACAACGA GGTGTTCT 12582
389 CCACCUCU G UGGAAAAA 5081 TTTTTCCA GGCTAGCTACAACGA AGAGGTGG 12583
399 GGAAAAAG G CAACUCGG 5082 CCGAGTTG GGCTAGCTACAACGA CTTTTTCC 12584
402 AAAAGGCA A CUCGGCGG 5256 CCGCCGAG GGCTAGCTACAACGA TGCCTTTT 12585
407 GCAACUCG G CGGUGAUG 5083 CATCACCG GGCTAGCTACAACGA CGAGTTGC 12586
410 ACUCGGCG G UGAUGGGC 5084 GCCCATCA GGCTAGCTACAACGA CGCCGAGT 12587
413 CGGCGGUG A UGGGCGGG 5257 CCCGCCCA GGCTAGCTACAACGA CACCGCCG 12588
417 GGUGAUGG G CGGGGUGC 5085 GCACCCCG GGCTAGCTACAACGA CCATCACC 12589
422 UGGGCGGG G UGCUCUUC 5086 GAAGAGCA GGCTAGCTACAACGA CCCGCCCA 12590
424 GGCGGGGU G CUCUUCAG 5087 CTGAAGAG GGCTAGCTACAACGA ACCCCGCC 12591
432 GCUCUUCA G CACCGGCC 5088 GGCCGGTG GGCTAGCTACAACGA TGAAGAGC 12592
434 UCUUCAGC A CCGGCCUC 4759 GAGGCCGG GGCTAGCTACAACGA GCTGAAGA 12593
438 CAGCACCG G CCUCCUGG 5089 CCAGGAGG GGCTAGCTACAACGA CGGTGCTG 12594
447 CCUCCUGG G CAACCUGC 5090 GCAGGTTG GGCTAGCTACAACGA CCAGGAGG 12595
450 CCUGGGCA A CCUGCUGG 5258 CCAGCAGG GGCTAGCTACAACGA TGCCCAGG 12596
454 GGCAACCU G CUGGCCCU 5091 AGGGCCAG GGCTAGCTACAACGA AGGTTGCC 12597
458 ACCUGCUG G CCCUGGGG 5092 CCCCAGGG GGCTAGCTACAACGA CAGCAGGT 12598
466 GCCCUGGG G CUGCUGGC 5093 GCCAGCAG GGCTAGCTACAACGA CCCAGGGC 12599
469 CUGGGGCU G CUGGCGCG 5094 CGCGCCAG GGCTAGCTACAACGA AGCCCCAG 12600
473 GGCUGCUG G CGCGCUCG 5095 CGAGCGCG GGCTAGCTACAACGA CAGCAGCC 12601
475 CUGCUGGC G CGCUCGGG 5096 CCCGAGCG GGCTAGCTACAACGA GCCAGCAG 12602
477 GCUGGCGC G CUCGGGGC 5097 GCCCCGAG GGCTAGCTACAACGA GCGCCAGC 12603
484 CGCUCGGG G CUGGGGUG 5098 CACCCCAG GGCTAGCTACAACGA CCCGAGCG 12604
490 GGGCUGGG G UGGUGCUC 5099 GAGCACCA GGCTAGCTACAACGA CCCAGCCC 12605
493 CUGGGGUG G UGCUCGCG 5100 CGCGAGCA GGCTAGCTACAACGA CACCCCAG 12606
495 GGGGUGGU G CUCGCGGC 5101 GCCGCGAG GGCTAGCTACAACGA ACCACCCC 12607
499 UGGUGCUC G CGGCGUCC 5102 GGACGCCG GGCTAGCTACAACGA GAGCACCA 12608
502 UGCUCGCG G CGUCCACU 5103 AGTGGACG GGCTAGCTACAACGA CGCGAGCA 12609
504 CUCGCGGC G UCCACUGC 5104 GCAGTGGA GGCTAGCTACAACGA GCCGCGAG 12610
508 CGGCGUCC A CUGCGCCC 4778 GGGCGCAG GGCTAGCTACAACGA GGACGCCG 12611
511 CGUCCACU G CGCCCGCU 5105 AGCGGGCG GGCTAGCTACAACGA AGTGGACG 12612
Figure imgf000274_0001
513 UCCACUGC G CCCGCUGC 5106 GCAGCGGG GGCTAGCTACAACGA GCAGTGGA 12613
517 CUGCGCCC G CUGCCCUC 5107 GAGGGCAG GGCTAGCTACAACGA GGGCGCAG 12614
520 CGCCCGCU G CCCUCGGU 5108 ACCGAGGG GGCTAGCTACAACGA AGCGGGCG 12615
527 UGCCCUCG G UCUUCUAC 5109 GTAGAAGA GGCTAGCTACAACGA CGAGGGCA 12616
534 GGUCUUCU A CAUGCUGG 4483 CCAGCATG GGCTAGCTACAACGA AGAAGACC 12617
536 UCUUCUAC A UGCUGGUG 4788 CACCAGCA GGCTAGCTACAACGA GTAGAAGA 12618
538 UUCUACAU G CUGGUGUG 5110 CACACCAG GGCTAGCTACAACGA ATGTAGAA 12619
542 ACAUGCUG G UGUGUGGC 5111 GCCACACA GGCTAGCTACAACGA CAGCATGT 12620
544 AUGCUGGU G UGUGGCCU 5112 AGGCCACA GGCTAGCTACAACGA ACCAGCAT 12621
546 GCUGGUGU G UGGCCUGA 5113 TCAGGCCA GGCTAGCTACAACGA ACACCAGC 12622
549 GGUGUGUG G CCUGACGG 5114 CCGTCAGG GGCTAGCTACAACGA CACACACC 12623
554 GUGGCCUG A CGGUCACC 5259 GGTGACCG GGCTAGCTACAACGA CAGGCCAC 12624
557 GCCUGACG G UCACCGAC 5115 GTCGGTGA GGCTAGCTACAACGA CGTCAGGC 12625
560 UGACGGUC A CCGACUUG 4792 CAAGTCGG GGCTAGCTACAACGA GACCGTCA 12626
564 GGUCACCG A CUUGCUGG 5260 CCAGCAAG GGCTAGCTACAACGA CGGTGACC 12627
568 ACCGACUU G CUGGGCAA 5116 TTGCCCAG GGCTAGCTACAACGA AAGTCGGT 12628
573 CUUGCUGG G CAAGUGCC 5117 GGCACTTG GGCTAGCTACAACGA CCAGCAAG 12629
577 CUGGGCAA G UGCCUCCU 5118 AGGAGGCA GGCTAGCTACAACGA TTGCCCAG 12630
579 GGGCAAGU G CCUCCUAA 5119 TTAGGAGG GGCTAGCTACAACGA ACTTGCCC 12631
588 CCUCCUAA G CCCGGUGG 5120 CCACCGGG GGCTAGCTACAACGA TTAGGAGG 12632
593 UAAGCCCG G UGGUGCUG 5121 CAGCACCA GGCTAGCTACAACGA CGGGCTTA 12633
596 GCCCGGUG G UGCUGGCU 5122 AGCCAGCA GGCTAGCTACAACGA CACCGGGC 12634
598 CCGGUGGU G CUGGCUGC 5123 GCAGCCAG GGCTAGCTACAACGA ACCACCGG 12635
602 UGGUGCUG G CUGCCUAC 5124 GTAGGCAG GGCTAGCTACAACGA CAGCACCA 12636
605 UGCUGGCU G CCUACGCU 5125 AGCGTAGG GGCTAGCTACAACGA AGCCAGCA 12637
609 GGCUGCCU A CGCUCAGA 4488 TCTGAGCG GGCTAGCTACAACGA AGGCAGCC 12638
611 CUGCCUAC G CUGAGAAC 5126 GTTCTGAG GGCTAGCTACAACGA GTAGGCAG 12639
618 CGCUCAGA A CCGGAGUC 5261 GACTCCGG GGCTAGCTACAACGA TCTGAGCG 12640
624 GAACCGGA G UCUGCGGG 5127 CCCGCAGA GGCTAGCTACAACGA TCCGGTTC 12641
628 CGGAGUCU G CGGGUGCU 5128 AGCACCCG GGCTAGCTACAACGA AGACTCCG 12642
632 GUCUGCGG G UGCUUGCG 5129 CGCAAGCA GGCTAGCTACAACGA CCGCAGAC 12643
634 CUGCGGGU G CUUGCGCC 5130 GGCGCAAG GGCTAGCTACAACGA ACCCGCAG 12644
638 GGGUGCUU G CGCCCGCA 5131 TGCGGGCG GGCTAGCTACAACGA AAGCACCC 12645
640 GUGCUUGC G CCCGCAUU 5132 AATGCGGG GGCTAGCTACAACGA GCAAGCAC 12646
644 UUGCGCCC G CAUUGGAC 5133 GTCCAATG GGCTAGCTACAACGA GGGCGCAA 12647
646 GCGCCCGC A UUGGACAA 4814 TTGTCCAA GGCTAGCTACAACGA GCGGGCGC 12648
651 CGCAUUGG A CAACUCGU 5262 ACGAGTTG GGCTAGCTACAACGA CCAATGCG 12649
Figure imgf000275_0001
654 AUUGGACA A CUCGUUGU 5263 ACAACGAG GGCTAGCTACAACGA TGTCCAAT 12650
658 GACAACUC G UUGUGCCA 5134 TGGCACAA GGCTAGCTACAACGA GAGTTGTC 12651
661 AACUCGUU G UGCCAAGC 5135 GCTTGGCA GGCTAGCTACAACGA AACGAGTT 12652
663 CUCGUUGU G CCAAGCCU 5136 AGGCTTGG GGCTAGCTACAACGA ACAACGAG 12653
668 UGUGCCAA G CCUUCGCC 5137 GGCGAAGG GGCTAGCTACAACGA TTGGCACA 12654
674 AAGCCUUC G CCUUCUUC 5138 GAAGAAGG GGCTAGCTACAACGA GAAGGCTT 12655
683 CCUUCUUC A UGUCCUUC 4824 GAAGGACA GGCTAGCTACAACGA GAAGAAGG 12656
685 UUCUUCAU G UCCUUCUU 5139 AAGAAGGA GGCTAGCTACAACGA ATGAAGAA 12657
697 UUCUUUGG G CUCUCCUC 5140 GAGGAGAG GGCTAGCTACAACGA CCAAAGAA 12658
707 UCUCCUCG A CACUGCAA 5264 TTGCAGTG GGCTAGCTACAACGA CGAGGAGA 12659
709 UCCUCGAC A CUGCAACU 4832 AGTTGCAG GGCTAGCTACAACGA GTCGAGGA 12660
712 UCGACACU G CAACUCCU 5141 AGGAGTTG GGCTAGCTACAACGA AGTGTCGA 12661
715 ACACUGCA A CUCCUGGC 5265 GCCAGGAG GGCTAGCTACAACGA TGCAGTGT 12662
722 AACUCCUG G CCAUGGCA 5142 TGCCATGG GGCTAGCTACAACGA CAGGAGTT 12663
725 UCCUGGCC A UGGCACUG 4839 CAGTGCCA GGCTAGCTACAACGA GGCCAGGA 12664
728 UGGCCAUG G CACUGGAG 5143 CTCCAGTG GGCTAGCTACAACGA CATGGCCA 12665
730 GCCAUGGC A CUGGAGUG 4840 CACTCCAG GGCTAGCTACAACGA GCCATGGC 12666
736 GCACUGGA G UGCUGGCU 5144 AGCCAGCA GGCTAGCTACAACGA TCCAGTGC 12667
738 ACUGGAGU G CUGGCUCU 5145 AGAGCCAG GGCTAGCTACAACGA ACTCCAGT 12668
742 GAGUGCUG G CUCUCCCU 5146 AGGGAGAG GGCTAGCTACAACGA CAGCACTC 12669
754 UCCCUAGG G CACCCUUU 5147 AAAGGGTG GGCTAGCTACAACGA CCTAGGGA 12670
756 CCUAGGGC A CCCUUUCU 4848 AGAAAGGG GGCTAGCTACAACGA GCCCTAGG 12671
768 UUUCUUCU A CCGACGGC 4518 GCCGTCGG GGCTAGCTACAACGA AGAAGAAA 12672
772 UUCUACCG A CGGCACAU 5266 ATGTGCCG GGCTAGCTACAACGA CGGTAGAA 12673
775 UACCGACG G CACAUCAC 5148 GTGATGTG GGCTAGCTACAACGA CGTCGGTA 12674
777 CCGACGGC A CAUCACCC 4855 GGGTGATG GGCTAGCTACAACGA GCCGTCGG 12675
779 GACGGCAC A UCACCCUG 4856 CAGGGTGA GGCTAGCTACAACGA GTGCCGTC 12676
782 GGCACAUC A CCCUGCGC 4857 GCGCAGGG GGCTAGCTACAACGA GATGTGCC 12677
787 AUCACCCU G CGCCUGGG 5149 CCCAGGCG GGCTAGCTACAACGA AGGGTGAT 12678
789 CACCCUGC G CCUGGGCG 5150 CGCCCAGG GGCTAGCTACAACGA GCAGGGTG 12679
795 GCGCCUGG G CGCACUGG 5151 CCAGTGCG GGCTAGCTACAACGA CCAGGCGC 12680
797 GCCUGGGC G CACUGGUG 5152 CACCAGTG GGCTAGCTACAACGA GCCCAGGC 12681
799 CUGGGCGC A CUGGUGGC 4863 GCCACCAG GGCTAGCTACAACGA GCGCCCAG 12682
803 GCGCACUG G UGGCCCCG 5153 CGGGGCCA GGCTAGCTACAACGA CAGTGCGC 12683
806 CACUGGUG G CCCCGGUG 5154 CACCGGGG GGCTAGCTACAACGA CACCAGTG 12684
812 UGGCCCCG G UGGUGAGC 5155 GCTCACCA GGCTAGCTACAACGA CGGGGCCA 12685
815 CCCCGGUG G UGAGCGCC 5156 GGCGCTCA GGCTAGCTACAACGA CACCGGGG 12686
Figure imgf000276_0001
819 GGUGGUGA G CGCCUUCU 5157 AGAAGGCG GGCTAGCTACAACGA TCACCACC 12687
821 UGGUGAGC G CCUUCUCC 5158 GGAGAAGG GGCTAGCTACAACGA GCTCACCA 12688
833 UCUCCCUG G CUUUCUGC 5159 GCAGAAAG GGCTAGCTACAACGA CAGGGAGA 12689
840 GGCUUUCU G CGCGCUAC 5160 GTAGCGCG GGCTAGCTACAACGA AGAAAGCC 12690
842 CUUUCUGC G CGCUACCU 5161 AGGTAGCG GGCTAGCTACAACGA GCAGAAAG 12691
844 UUCUGCGC G CUACCUUU 5162 AAAGGTAG GGCTAGCTACAACGA GCGCAGAA 12692
847 UGCGCGCU A CCUUUCAU 4526 ATGAAAGG GGCTAGCTACAACGA AGCGCGCA 12693
854 UACCUUUC A UGGGCUUC 4879 GAAGCCCA GGCTAGCTACAACGA GAAAGGTA 12694
858 UUUCAUGG G CUUCGGGA 5163 TCCCGAAG GGCTAGCTACAACGA CCATGAAA 12695
868 UUCGGGAA G UUCGUGCA 5164 TGCACGAA GGCTAGCTACAACGA TTCCCGAA 12696
872 GGAAGUUC G UGCAGUAC 5165 GTACTGCA GGCTAGCTACAACGA GAACTTCC 12697
874 AAGUUCGU G CAGUACUG 5166 CAGTACTG GGCTAGCTACAACGA ACGAACTT 12698
877 UUCGUGCA G UACUGCCC 5167 GGGCAGTA GGCTAGCTACAACGA TGCACGAA 12699
879 CGUGCAGU A CUGCCCCG 4534 CGGGGCAG GGCTAGCTACAACGA ACTGCACG 12700
882 GCAGUACU G CCCCGGCA 5168 TGCCGGGG GGCTAGCTACAACGA AGTACTGC 12701
888 CUGCCCCG G CACCUGGU 5169 ACCAGGTG GGCTAGCTACAACGA CGGGGCAG 12702
890 GCCCCGGC A CCUGGUGC 4886 GCACCAGG GGCTAGCTACAACGA GCCGGGGC 12703
895 GGCACCUG G UGCUUUAU 5170 ATAAAGCA GGCTAGCTACAACGA CAGGTGCC 12704
897 CACCUGGU G CUUUAUCC 5171 GGATAAAG GGCTAGCTACAACGA ACCAGGTG 12705
902 GGUGCUUU A UCCAGAUG 4537 CATCTGGA GGCTAGCTACAACGA AAAGCACC 12706
908 UUAUCCAG A UGGUCCAC 5267 GTGGACCA GGCTAGCTACAACGA CTGGATAA 12707
911 UCCAGAUG G UCCACGAG 5172 CTCGTGGA GGCTAGCTACAACGA CATCTGGA 12708
915 GAUGGUCC A CGAGGAGG 4893 CCTCCTCG GGCTAGCTACAACGA GGACCATC 12709
924 CGAGGAGG G CUCGCUGU 5173 ACAGCGAG GGCTAGCTACAACGA CCTCCTCG 12710
928 GAGGGCUC G CUGUCGGU 5174 ACCGACAG GGCTAGCTACAACGA GAGCCCTC 12711
931 GGCUCGCU G UCGGUGCU 5175 AGCACCGA GGCTAGCTACAACGA AGCGAGCC 12712
935 CGCUGUCG G UGCUGGGG 5176 CCCCAGCA GGCTAGCTACAACGA CGACAGCG 12713
937 CUGUCGGU G CUGGGGUA 5177 TACCCCAG GGCTAGCTACAACGA ACCGACAG 12714
943 GUGCUGGG G UACUCUGU 5178 ACAGAGTA GGCTAGCTACAACGA CCCAGCAC 12715
945 GCUGGGGU A CUCUGUGC 4542 GCACAGAG GGCTAGCTACAACGA ACCCCAGC 12716
950 GGUACUCU G UGCUCUAC 5179 GTAGAGCA GGCTAGCTACAACGA AGAGTACC 12717
952 UACUCUGU G CUCUACUC 5180 GAGTAGAG GGCTAGCTACAACGA ACAGAGTA 12718
957 UGUGCUCU A CUCCAGCC 4545 GGCTGGAG GGCTAGCTACAACGA AGAGCACA 12719
963 CUACUCCA G CCUCAUGG 5181 CCATGAGG GGCTAGCTACAACGA TGGAGTAG 12720
968 CCAGCCUC A UGGCGCUG 4906 CAGCGCCA GGCTAGCTACAACGA GAGGCTGG 12721
971 GCCUCAUG G CGCUGCUG 5182 CAGCAGCG GGCTAGCTACAACGA CATGAGGC 12722
973 CUCAUGGC G CUGCUGGU 5183 ACCAGCAG GGCTAGCTACAACGA GCCATGAG 12723
Figure imgf000277_0001
976 AUGGCGCU G CUGGUCCU 5184 AGGACCAG GGCTAGCTACAACGA AGCGCCAT 12724
980 CGCUGCUG G UCCUCGCC 5185 GGCGAGGA GGCTAGCTACAACGA CAGCAGCG 12725
986 UGGUCCUC G CCACCGUG 5186 CACGGTGG GGCTAGCTACAACGA GAGGACCA 12726
989 UCCUCGCC A CCGUGCUG 4912 CAGCACGG GGCTAGCTACAACGA GGCGAGGA 12727
992 UCGCCACC G UGCUGUGC 5187 GCACAGCA GGCTAGCTACAACGA GGTGGCGA 12728
994 GCCACCGU G CUGUGCAA 5188 TTGCACAG GGCTAGCTACAACGA ACGGTGGC 12729
997 ACCGUGCU G UGCAACCU 5189 AGGTTGCA GGCTAGCTACAACGA AGCACGGT 12730
999 CGUGCUGU G CAACCUCG 5190 CGAGGTTG GGCTAGCTACAACGA ACAGCACG 12731
1002 GCUGUGCA A CCUCGGCG 5268 CGCCGAGG GGCTAGCTACAACGA TGCACAGC 12732
1008 CAACCUCG G CGCCAUGC 5191 GCATGGCG GGCTAGCTACAACGA CGAGGTTG 12733
1010 ACCUCGGC G CCAUGCGC 5192 GCGCATGG GGCTAGCTACAACGA GCCGAGGT 12734
1013 UCGGCGCC A UGCGCAAC 4919 GTTGCGCA GGCTAGCTACAACGA GGCGCCGA 12735
1015 GGCGCCAU G CGCAACCU 5193 AGGTTGCG GGCTAGCTACAACGA ATGGCGCC 12736
1017 CGCCAUGC G CAACCUCU 5194 AGAGGTTG GGCTAGCTACAACGA GCATGGCG 12737
1020 CAUGCGCA A CCUCUAUG 5269 CATAGAGG GGCTAGCTACAACGA TGCGCATG 12738
1026 CAACCUCU A UGCGAUGC 4552 GCATCGCA GGCTAGCTACAACGA AGAGGTTG 12739
1028 ACCUCUAU G CGAUGCAC 5195 GTGCATCG GGCTAGCTACAACGA ATAGAGGT 12740
1031 UCUAUGCG A UGCACCGG 5270 CCGGTGCA GGCTAGCTACAACGA CGCATAGA 12741
1033 UAUGCGAU G CACCGGCG 5196 CGCCGGTG GGCTAGCTACAACGA ATCGCATA 12742
1035 UGCGAUGC A CCGGCGGC 4924 GCCGCCGG GGCTAGCTACAACGA GCATCGCA 12743
1039 AUGCACCG G CGGCUGCA 5197 TGCAGCCG GGCTAGCTACAACGA CGGTGCAT 12744
1042 CACCGGCG G CUGCAGCG 5198 CGCTGCAG GGCTAGCTACAACGA CGCCGGTG 12745
1045 CGGCGGCU G CAGCGGCA 5199 TGCCGCTG GGCTAGCTACAACGA AGCCGCCG 12746
1048 CGGCUGCA G CGGCACCC 5200 GGGTGCCG GGCTAGCTACAACGA TGCAGCCG 12747
1051 CUGCAGCG G CACCCGCG 5201 CGCGGGTG GGCTAGCTACAACGA CGCTGCAG 12748
1053 GCAGCGGC A CCCGCGCU 4928 AGCGCGGG GGCTAGCTACAACGA GCCGCTGC 12749
1057 CGGCACCC G CGCUCCUG 5202 CAGGAGCG GGCTAGCTACAACGA GGGTGCCG 12750
1059 GCACCCGC G CUCCUGCA 5203 TGCAGGAG GGCTAGCTACAACGA GCGGGTGC 12751
1065 GCGCUCCU G CACCAGGG 5204 CCCTGGTG GGCTAGCTACAACGA AGGAGCGC 12752
1067 GCUCCUGC A CCAGGGAC 4934 GTCCCTGG GGCTAGCTACAACGA GCAGGAGC 12753
1074 CACCAGGG A CUGUGCCG 5271 CGGCACAG GGCTAGCTACAACGA CCCTGGTG 12754
1077 CAGGGACU G UGCCGAGC 5205 GCTCGGCA GGCTAGCTACAACGA AGTCCCTG 12755
1079 GGGACUGU G CCGAGCCG 5206 CGGCTCGG GGCTAGCTACAACGA ACAGTCCC 12756
1084 UGUGCCGA G CCGCGCGC 5207 GCGCGCGG GGCTAGCTACAACGA TCGGCACA 12757
1087 GCCGAGCC G CGCGCGGA 5208 TCCGCGCG GGCTAGCTACAACGA GGCTCGGC 12758
1089 CGAGCCGC G CGCGGACG 5209 CGTCCGCG GGCTAGCTACAACGA GCGGCTCG 12759
1091 AGCCGCGC G CGGACGGG 5210 CCCGTCCG GGCTAGCTACAACGA GCGCGGCT 12760
Figure imgf000278_0001
1095 GCGCGCGG A CGGGAGGG 5272 CCCTCCCG GGCTAGCTACAACGA CCGCGCGC 12761
1106 GGAGGGAA G CGUCCCCU 5211 AGGGGACG GGCTAGCTACAACGA TTCCCTCC 12762
1108 AGGGAAGC G UCCCCUCA 5212 TGAGGGGA GGCTAGCTACAACGA GCTTCCCT 12763
1117 UCCCCUCA G CCCCUGGA 5213 TCCAGGGG GGCTAGCTACAACGA TGAGGGGA 12764
1129 CUGGAGGA G CUGGAUCA 5214 TGATCCAG GGCTAGCTACAACGA TCCTCCAG 12765
1134 GGAGCUGG A UCACCUCC 5273 GGAGGTGA GGCTAGCTACAACGA CCAGCTCC 12766
1137 GCUGGAUC A CCUCCUGC 4950 GCAGGAGG GGCTAGCTACAACGA GATCCAGC 12767
1144 CACCUCCU G CUGCUGGC 5215 GCCAGCAG GGCTAGCTACAACGA AGGAGGTG 12768
1147 CUCCUGCU G CUGGCGCU 5216 AGCGCCAG GGCTAGCTACAACGA AGCAGGAG 12769
1151 UGCUGCUG G CGCUGAUG 5217 CATCAGCG GGCTAGCTACAACGA CAGCAGCA 12770
1153 CUGCUGGC G CUGAUGAC 5218 GTCATCAG GGCTAGCTACAACGA GCCAGCAG 12771
1157 UGGCGCUG A UGACCGUG 5274 CACGGTCA GGCTAGCTACAACGA CAGCGCCA 12772
1160 CGCUGAUG A CCGUGCUC 5275 GAGCACGG GGCTAGCTACAACGA CATCAGCG 12773
1163 UGAUGACC G UGCUCUUC 5219 GAAGAGCA GGCTAGCTACAACGA GGTCATCA 12774
1165 AUGACCGU G CUCUUCAC 5220 GTGAAGAG GGCTAGCTACAACGA ACGGTCAT 12775
1172 UGCUCUUC A CUAUGUGU 4961 ACACATAG GGCTAGCTACAACGA GAAGAGCA 12776
1175 UCUUCACU A UGUGUUCU 4561 AGAACACA GGCTAGCTACAACGA AGTGAAGA 12777
1177 UUCACUAU G UGUUCUCU 5221 AGAGAACA GGCTAGCTACAACGA ATAGTGAA 12778
1179 CACUAUGU G UUCUCUGC 5222 GCAGAGAA GGCTAGCTACAACGA ACATAGTG 12779
1186 UGUUCUCU G CCCGUAAU 5223 ATTACGGG GGCTAGCTACAACGA AGAGAACA 12780
1190 CUCUGCCC G UAAUUUAU 5224 ATAAATTA GGCTAGCTACAACGA GGGCAGAG 12781
1193 UGCCCGUA A UUUAUCGC 5276 GCGATAAA GGCTAGCTACAACGA TACGGGCA 12782
1197 CGUAAUUU A UCGCGCUU 4568 AAGCGCGA GGCTAGCTACAACGA AAATTACG 12783
1200 AAUUUAUC G CGCUUACU 5225 AGTAAGCG GGCTAGCTACAACGA GATAAATT 12784
1202 UUUAUCGC G CUUACUAU 5226 ATAGTAAG GGCTAGCTACAACGA GCGATAAA 12785
1206 UCGCGCUU A CUAUGGAG 4571 CTCCATAG GGCTAGCTACAACGA AAGCGCGA 12786
1209 CGCUUACU A UGGAGCAU 4572 ATGCTCCA GGCTAGCTACAACGA AGTAAGCG 12787
1214 ACUAUGGA G CAUUUAAG 5227 CTTAAATG GGCTAGCTACAACGA TCCATAGT 12788
1216 UAUGGAGC A UUUAAGGA 4969 TCCTTAAA GGCTAGCTACAACGA GCTCCATA 12789
1224 AUUUAAGG A UGUCAAGG 5277 CCTTGACA GGCTAGCTACAACGA CCTTAAAT 12790
1226 UUAAGGAU G UCAAGGAG 5228 CTCCTTGA GGCTAGCTACAACGA ATCCTTAA 12791
1239 GGAGAAAA A CAGGACCU 5278 AGGTCCTG GGCTAGCTACAACGA TTTTCTCC 12792
1244 AAAACAGG A CCUCUGAA 5279 TTCAGAGG GGCTAGCTACAACGA CCTGTTTT 12793
1256 CUGAAGAA G CAGAAGAC 5229 GTCTTCTG GGCTAGCTACAACGA TTCTTCAG 12794
1263 AGCAGAAG A CCUCCGAG 5280 CTCGGAGG GGCTAGCTACAACGA CTTCTGCT 12795
1271 ACCUCCGA G CCUUGCGA 5230 TCGCAAGG GGCTAGCTACAACGA TCGGAGGT 12796
1276 CGAGCCUU G CGAUUUCU 5231 AGAAATCG GGCTAGCTACAACGA AAGGCTCG 12797
Figure imgf000279_0001
1279 GCCUUGCG A UUUCUAUC 5281 GATAGAAA GGCTAGCTACAACGA CGCAAGGC 12798
1285 CGAUUUCU A UCUGUGAU 4583 ATCACAGA GGCTAGCTACAACGA AGAAATCG 12799
1289 UUCUAUCU G UGAUUUCA 5232 TGAAATCA GGCTAGCTACAACGA AGATAGAA 12800
1292 UAUCUGUG A UUUCAAUU 5282 AATTGAAA GGCTAGCTACAACGA CACAGATA 12801
1298 UGAUUUCA A UUGUGGAC 5283 GTCCACAA GGCTAGCTACAACGA TGAAATCA 12802
1301 UUUCAAUU G UGGACCCU 5233 AGGGTCCA GGCTAGCTACAACGA AATTGAAA 12803
1305 AAUUGUGG A CCCUUGGA 5284 TCCAAGGG GGCTAGCTACAACGA CCACAATT 12804
1313 ACCCUUGG A UUUUUAUC 5285 GATAAAAA GGCTAGCTACAACGA CCAAGGGT 12805
1319 GGAUUUUU A UCAUUUUC 4594 GAAAATGA GGCTAGCTACAACGA AAAAATCC 12806
1322 UUUUUAUC A UUUUCAGA 4987 TCTGAAAA GGCTAGCTACAACGA GATAAAAA 12807
1330 AUUUUCAG A UCUCCAGU 5286 ACTGGAGA GGCTAGCTACAACGA CTGAAAAT 12808
1337 GAUCUCCA G UAUUUCGG 5234 CCGAAATA GGCTAGCTACAACGA TGGAGATC 12809
1339 UCUCCAGU A UUUCGGAU 4602 ATCCGAAA GGCTAGCTACAACGA ACTGGAGA 12810
1346 UAUUUCGG A UAUUUUUU 5287 AAAAAATA GGCTAGCTACAACGA CCGAAATA 12811
1348 UUUCGGAU A UUUUUUCA 4606 TGAAAAAA GGCTAGCTACAACGA ATCCGAAA 12812
1356 AUUUUUUC A CAAGAUUU 4992 AAATCTTG GGCTAGCTACAACGA GAAAAAAT 12813
1361 UUCACAAG A UUUUCAUU 5288 AATGAAAA GGCTAGCTACAACGA CTTGTGAA 12814
1367 AGAUUUUC A UUAGACCU 4994 AGGTCTAA GGCTAGCTACAACGA GAAAATCT 12815
1372 UUCAUUAG A CCUCUUAG 5289 CTAAGAGG GGCTAGCTACAACGA CTAATGAA 12816
1381 CCUCUUAG G UACAGGAG 5235 CTCCTGTA GGCTAGCTACAACGA CTAAGAGG 12817
1383 UCUUAGGU A CAGGAGCC 4622 GGCTCCTG GGCTAGCTACAACGA ACCTAAGA 12818
1389 GUACAGGA G CCGGUGCA 5236 TGCACCGG GGCTAGCTACAACGA TCCTGTAC 12819
1393 AGGAGCCG G UGCAGGAA 5237 TTGCTGCA GGCTAGCTACAACGA CGGCTCCT 12820
1395 GAGCCGGU G CAGCAAUU 5238 AATTGCTG GGCTAGCTACAACGA ACCGGCTC 12821
1398 CCGGUGCA G CAAUUCCA 5239 TGGAATTG GGCTAGCTACAACGA TGCACCGG 12822
1401 GUGCAGCA A UUCCACUA 5290 TAGTGGAA GGCTAGCTACAACGA TGCTGCAC 12823
1406 GCAAUUCC A CUAACAUG 5003 CATGTTAG GGCTAGCTACAACGA GGAATTGC 12824
1410 UUCCACUA A CAUGGAAU 5291 ATTCCATG GGCTAGCTACAACGA TAGTGGAA 12825
1412 CCACUAAC A UGGAAUCC 5005 GGATTCCA GGCTAGCTACAACGA GTTAGTGG 12826
1417 AACAUGGA A UCCAGUCU 5292 AGACTGGA GGCTAGCTACAACGA TCCATGTT 12827
1422 GGAAUCCA G UCUGUGAC 5240 GTCACAGA GGCTAGCTACAACGA TGGATTCC 12828
1426 UCCAGUCU G UGACAGUG 5241 CACTGTCA GGCTAGCTACAACGA AGACTGGA 12829
1429 AGUCUGUG A CAGUGUUU 5293 AAACACTG GGCTAGCTACAACGA CACAGACT 12830
1432 CUGUGACA G UGUUUUUC 5242 GAAAAACA GGCTAGCTACAACGA TGTCACAG 12831
1434 GUGACAGU G UUUUUCAC 5243 GTGAAAAA GGCTAGCTACAACGA ACTGTCAC 12832
1441 UGUUUUUC A CUCUGUGG 5010 CCACAGAG GGCTAGCTACAACGA GAAAAACA 12833
1446 UUCACUCU G UGGUAAGC 5244 GCTTACCA GGCTAGCTACAACGA AGAGTGAA 12834
Figure imgf000280_0001
1449 ACUCUGUG G UAAGCUGA 5245 TCAGCTTA GGCTAGCTACAACGA CACAGAGT 12835
1453 UGUGGUAA G CUGAGGAA 5246 TTCCTCAG GGCTAGCTACAACGA TTACCACA 12836
1461 GCUGAGGA A UAUGUCAC 5294 GTGACATA GGCTAGCTACAACGA TCCTCAGC 12837
1463 UGAGGAAU A UGUCACAU 4635 ATGTGACA GGCTAGCTACAACGA ATTCCTCA 12838
1465 AGGAAUAU G UCACAUUU 5247 AAATGTGA GGCTAGCTACAACGA ATATTCCT 12839
1468 AAUAUGUC A CAUUUUCA 5014 TGAAAATG GGCTAGCTACAACGA GACATATT 12840
1470 UAUGUCAC A UUUUCAGU 5015 ACTGAAAA GGCTAGCTACAACGA GTGACATA 12841
1477 CAUUUUCA G UCAAAGAA 5248 TTCTTTGA GGCTAGCTACAACGA TGAAAATG 12842
Input Sequence = PTGDR_composit . Cut Site = R/Y
Arm Length = 8. Core Sequence = GGCTAGCTACAACGA
PTGDR_composit (1 to 993 of HSU31332 (PTGDR 51) + 1 to 495 of HSU31099
(PTGDR 3' ) ; 1488 nt)
Table XXIII: Human PTGDR Amberzyme and Substrate Sequence
Seq
Pos Substrate ID Amberzyme Seq ID
9 GAAUUCUG G CUAUUUUC 5018 GAAAAUAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGAAUUC 12843
23 UUCCUCCU G CCGUUCCG 5019 CGGAACGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGAGGAA 12844
Figure imgf000281_0001
26 CUCCUGCC G UUCCGACU 5020 AGUCGGAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGCAGGAG 12845
31 GCCGUUCC G ACUCGGCA 5295 UGCCGAGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGAACGGC 12846
36 UCCGACUC G GCACCAGA 5296 UCUGGUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GAGUCGGA 12847
37 CCGACUCG G CACCAGAG 5021 CUCUGGUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGAGUCGG 12848
43 CGGCACCA G AGUCUGUC 5297 GACAGACU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGUGCCG 12849
45 GCACCAGA G UCUGUCUC 5022 GAGACAGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUGGUGC 12850
49 CAGAGUCU G UCUCUACU 5023 AGUAGAGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGACUCUG 12851
58 UCUCUACU G AGAACGCA 5298 UGCGUUCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGUAGAGA 12852
60 UCUACUGA G AACGCAGC 5299 GCUGCGUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCAGUAGA 12853
64 CUGAGAAC G CAGCGCGU 5024 ACGCGCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GUUCUCAG 12854
67 AGAACGCA G CGCGUCAG 5025 CUGACGCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCGUUCU 12855
69 AACGCAGC G CGUCAGGG 5026 CCCUGACG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCUGCGUU 12856
71 CGCAGCGC G UCAGGGCC 5027 GGCCCUGA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCGCUGCG 12857
75 GCGCGUCA G GGCCGAGC 5300 GCUCGGCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGACGCGC 12858
76 CGCGUCAG G GCCGAGCU 5301 AGCUCGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUGACGCG 12859
77 GCGUCAGG G CCGAGCUC 5028 GAGCUCGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCUGACGC 12860
80 UCAGGGCC G AGCUCUUC 5302 GAAGAGCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGCCCUGA 12861
82 AGGGCCGA G CUCUUCAC 5029 GUGAAGAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCGGCCCU 12862
92 UCUUCACU G GCCUGCUC 5303 GAGCAGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGUGAAGA 12863
93 CUUCACUG G CCUGCUCC 5030 GGAGCAGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGUGAAG 12864
97 ACUGGCCU G CUCCGCGC 5031 GCGCGGAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGCCAGU 12865
102 CCUGCUCC G CGCUCUUC 5032 GAAGAGCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGAGCAGG 12866
104 UGCUCCGC G CUCUUCAA 5033 UUGAAGAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCGGAGCA 12867
114 UCUUCAAU G CCAGCGCC 5034 GGCGCUGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUUGAAGA 12868
118 GAAUGCCA G CGCCAGGC 5035 GCCUGGCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGCAUUG 12869
120 AUGCCAGC G CCAGGCGC 5036 GCGCCUGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCUGGCAU 12870
124 CAGCGCCA G GCGCUCAC 5304 GUGAGCGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGCGCUG 12871
125 AGCGCCAG G CGCUCACC 5037 GGUGAGCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUGGCGCU 12872
127 CGCCAGGC G CUCACCCU 5038 AGGGUGAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCCUGGCG 12873
136 CUCACCCU G CAGAGCGU 5039 ACGCUCUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGGUGAG 12874
139 ACCCUGCA G AGCGUCCC 5305 GGGACGCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGCAGGGU 12875
141 CCUGGAGA G CGUCCCGC 5040 GCGGGACG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUGCAGG 12876
143 UGCAGAGC G UCCCGCCU 5041 AGGCGGGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCUCUGCA 12877
148 AGCGUCCC G CCUCUCAA 5042 UUGAGAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGGACGCU 12878
158 CUCUCAAA G AGGGGUGU 5306 ACACCCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUGAGAG 12879
160 CUCAAAGA G GGGUGUGA 5307 UCACACCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUUUGAG 12880
161 UCAAAGAG G GGUGUGAC 5308 GUCACACC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCUUUGA 12881
Figure imgf000282_0001
162 CAAAGAGG G GUGUGACC 5309 GGUCACAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCUCUUUG 12882
163 AAAGAGGG G UGUGACCC 5043 GGGUCACA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCUCUUU 12883
165 AGAGGGGU G UGACCCGC 5044 GCGGGUCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACCCCUCU 12884
167 AGGGGUGU G ACCCGCGA 5310 UCGCGGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACACCCCU 12885
172 UGUGACCC G CGAGUUUA 5045 UAAACUCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGGUCACA 12886
174 UGACCCGC G AGUUUAGA 5311 UCUAAACU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCGGGUCA 12887
176 ACCCGCGA G UUUAGAUA 5046 UAUCUAAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCGCGGGU 12888
181 CGAGUUUA G AUAGGAGG 5312 CCUCCUAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UAAACUCG 12889
185 UUUAGAUA G GAGGUUCC 5313 GGAACCUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UAUCUAAA 12890
186 UUAGAUAG G AGGUUCCU 5314 AGGAACCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUAUCUAA 12891
188 AGAUAGGA G GUUCCUGC 5315 GCAGGAAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCUAUCU 12892
189 GAUAGGAG G UUCCUGCC 5047 GGCAGGAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUCCUAUC 12893
195 AGGUUCCU G CCGUGGGG 5048 CCCCACGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGAACCU 12894
198 UUCCUGCC G UGGGGAAC 5049 GUUCCCCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGCAGGAA 12895
200 CCUGCCGU G GGGAACAC 5316 GUGUUCCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACGGCAGG 12896
201 CUGCCGUG G GGAACACC 5317 GGUGUUCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CACGGCAG 12897
202 UGCCGUGG G GAACACCC 5318 GGGUGUUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCACGGCA 12898
203 GCCGUGGG G AACACCCC 5319 GGGGUGUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCCACGGC 12899
212 AACACCCC G CCGCCCUC 5050 GAGGGCGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGGGUGUU 12900
215 ACCCCGCC G CCCUCGGA 5051 UCCGAGGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGCGGGGU 12901
221 CCGCCCUC G GAGCUUUU 5320 AAAAGCUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GAGGGCGG 12902
222 CGCCCUCG G AGCUUUUU 5321 AAAAAGCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGAGGGCG 12903
224 CCCUCGGA G CUUUUUCU 5052 AGAAAAAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCGAGGG 12904
233 CUUUUUCU G UGGCGCAG 5053 CUGCGCCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGAAAAAG 12905
235 UUUUCUGU G GCGCAGCU 5322 AGCUGCGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACAGAAAA 12906
236 UUUCUGUG G CGCAGCUU 5054 AAGCUGCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CACAGAAA 12907
238 UCUGUGGC G CAGCUUCU 5055 AGAAGCUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCCACAGA 12908
241 GUGGCGCA G CUUCUCCG 5056 CGGAGAAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGCGCCAC 12909
249 GCUUCUCC G CCCGAGCC 5057 GGCUCGGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGAGAAGC 12910
253 CUCCGCCC G AGCCGCGC 5323 GCGCGGCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGGCGGAG 12911
255 CCGCCCGA G CCGCGCGC 5058 GCGCGCGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCGGGCGG 12912
258 CCCGAGCC G CGCGCGGA 5059 UCCGCGCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGCUCGGG 12913
260 CGAGCCGC G CGCGGAGC 5060 GCUCCGCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCGGCUCG 12914
262 AGCCGCGC G CGGAGCUG 5061 CAGCUCCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCGCGGCU 12915
264 CCGCGCGC G GAGCUGCC 5324 GGCAGCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCGCGCGG 12916
265 CGCGCGCG G AGCUGCCG 5325 CGGCAGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGCGCGCG 12917
267 CGCGCGGA G CUGCCGGG 5062 CCCGGCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCGCGCG 12918
Figure imgf000283_0001
270 GCGGAGCU G CCGGGGGC 5063 GCCCCCGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCUCCGC 12919
273 GAGCUGCC G GGGGCUCC 5326 GGAGCCCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGCAGCUC 12920
274 AGCUGCCG G GGGCUCCU 5327 AGGAGCCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGGCAGCU 12921
275 GCUGCCGG G GGCUCCUU 5328 AAGGAGCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCGGCAGC 12922
276 CUGCCGGG G GCUCCUUA 5329 UAAGGAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCGGCAG 12923
277 UGCCGGGG G CUCCUUAG 5064 CUAAGGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCCGGCA 12924
285 GCUCCUUA G CACCCGGG 5065 CCCGGGUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UAAGGAGC 12925
291 UAGCACCC G GGCGCCGG 5330 CCGGCGCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGGUGCUA 12926
292 AGCACCCG G GCGCCGGG 5331 CCCGGCGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGGGUGCU 12927
293 GCACCCGG G CGCCGGGG 5066 CCCCGGCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCGGGUGC 12928
295 ACCCGGGC G CCGGGGCC 5067 GGCCCCGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCCCGGGU 12929
298 CGGGCGCC G GGGCCCUC 5332 GAGGGCCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGCGCCCG 12930
299 GGGCGCCG G GGCCCUCG 5333 CGAGGGCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGGCGCCC 12931
300 GGCGCCGG G GCCCUCGC 5334 GCGAGGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCGGCGCC 12932
301 GCGCCGGG G CCCUCGCC 5068 GGCGAGGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCCGGCGC 12933
307 GGGCCCUC G CCCUUCCG 5069 CGGAAGGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GAGGGCCC 12934
315 GCCCUUCC G CAGCCUUC 5070 GAAGGCUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGAAGGGC 12935
318 CUUCCGCA G CCUUCACU 5071 AGUGAAGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGCGGAAG 12936
330 UCACUCCA G CCCUCUGC 5072 GCAGAGGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGAGUGA 12937
337 AGCCCUCU G CUCCCGCA 5073 UGCGGGAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGAGGGCU 12938
343 CUGCUCCC G CACGCCAU 5074 AUGGCGUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGGAGCAG 12939
347 UCCCGCAC G CCAUGAAG 5075 CUUCAUGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GUGCGGGA 12940
352 CACGCCAU G AAGUCGCC 5335 GGCGACUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUGGCGUG 12941
355 GCCAUGAA G UCGCCGUU 5076 AACGGCGA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUCAUGGC 12942
358 AUGAAGUC G CCGUUCUA 5077 UAGAACGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GACUUCAU 12943
361 AAGUCGCC G UUCUACCG 5078 CGGUAGAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGCGACUU 12944
369 GUUCUACC G CUGCCAGA 5079 UCUGGCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGUAGAAC 12945
372 CUACCGCU G CCAGAACA 5080 UGUUCUGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCGGUAG 12946
376 CGCUGCCA G AACACCAC 5336 GUGGUGUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGCAGCG 12947
389 CCACCUCU G UGGAAAAA 5081 UUUUUCCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGAGGUGG 12948
391 ACCUCUGU G GAAAAAGG 5337 CCUUUUUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACAGAGGU 12949
392 CCUCUGUG G AAAAAGGC 5338 GCCUUUUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CACAGAGG 12950
398 UGGAAAAA G GCAACUCG 5339 CGAGUUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUUUCCA 12951
399 GGAAAAAG G CAACUCGG 5082 CCGAGUUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUUUUCC 12952
406 GGCAACUC G GCGGUGAU 5340 AUCACCGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GAGUUGCC 12953
407 GCAACUCG G CGGUGAUG 5083 CAUCACCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGAGUUGC 12954
409 AACUCGGC G GUGAUGGG 5341 CCCAUCAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCCGAGUU 12955
Figure imgf000284_0001
410 ACUCGGCG G UGAUGGGC 5084 GCCCAUCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGCCGAGU 12956
412 UCGGCGGU G AUGGGCGG 5342 CCGCCCAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACCGCCGA 12957
415 GCGGUGAU G GGCGGGGU 5343 ACCCCGCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUCACCGC 12958
416 CGGUGAUG G GCGGGGUG 5344 CACCCCGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUCACCG 12959
417 GGUGAUGG G CGGGGUGC 5085 GCACCCCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCAUCACC 12960
419 UGAUGGGC G GGGUGCUC 5345 GAGCACCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCCCAUCA 12961
420 GAUGGGCG G GGUGCUCU 5346 AGAGCACC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGCCCAUC 12962
421 AUGGGCGG G GUGCUCUU 5347 AAGAGCAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCGCCCAU 12963
422 UGGGCGGG G UGCUCUUC 5086 GAAGAGCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCCGCCCA 12964
424 GGCGGGGU G CUCUUCAG 5087 CUGAAGAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACCCCGCC 12965
432 GCUCUUCA G CACCGGCC 5088 GGCCGGUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGAAGAGC 12966
437 UCAGCACC G GCCUCCUG 5348 CAGGAGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGUGCUGA 12967
438 CAGCACCG G CCUCCUGG 5089 CCAGGAGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGGUGCUG 12968
445 GGCCUCCU G GGCAACCU 5349 AGGUUGCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGAGGCC 12969
446 GCCUCCUG G GCAACCUG 5350 CAGGUUGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGGAGGC 12970
447 CCUCCUGG G CAACCUGC 5090 GCAGGUUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCAGGAGG 12971
454 GGCAACCU G CUGGCCCU 5091 AGGGCCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGUUGCC 12972
457 AACCUGCU G GCCCUGGG 5351 CCCAGGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCAGGUU 12973
458 ACCUGCUG G CCCUGGGG 5092 CCCCAGGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGCAGGU 12974
463 CUGGCCCU G GGGCUGCU 5352 AGCAGCCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGGCCAG 12975
464 UGGCCCUG G GGCUGCUG 5353 CAGCAGCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGGGCCA 12976
465 GGCCCUGG G GCUGCUGG 5354 CCAGCAGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCAGGGCC 12977
466 GCCCUGGG G CUGCUGGC 5093 GCCAGCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCCAGGGC 12978
469 CUGGGGCU G CUGGCGCG 5094 CGCGCCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCCCCAG 12979
472 GGGCUGCU G GCGCGCUC 5355 GAGCGCGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCAGCCC 12980
473 GGCUGCUG G CGCGCUCG 5095 CGAGCGCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGCAGCC 12981
475 CUGCUGGC G CGCUCGGG 5096 CCCGAGCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCCAGCAG 12982
477 GCUGGCGC G CUCGGGGC 5097 GCCCCGAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCGCCAGC 12983
481 GCGCGCUC G GGGCUGGG 5356 CCCAGCCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GAGCGCGC 12984
482 CGCGCUCG G GGCUGGGG 5357 CCCCAGCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGAGCGCG 12985
483 GCGCUCGG G GCUGGGGU 5358 ACCCCAGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCGAGCGC 12986
484 CGCUCGGG G CUGGGGUG 5098 CACCCCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCGAGCG 12987
487 UCGGGGCU G GGGUGGUG 5359 CACCACCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCCCCGA 12988
488 CGGGGCUG G GGUGGUGC 5360 GCACCACC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGCCCCG 12989
489 GGGGCUGG G GUGGUGCU 5361 AGCACCAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCAGCCCC 12990
490 GGGCUGGG G UGGUGCUC 5099 GAGCACCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCAGCCC 12991
492 GCUGGGGU G GUGCUCGC 5362 GCGAGCAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACCCCAGC 12992
Figure imgf000285_0001
493 CUGGGGUG G UGCUCGCG 5100 CGCGAGCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CACCCCAG 12993
495 GGGGUGGU G CUCGCGGC 5101 GCCGCGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACCACCCC 12994
499 UGGUGCUC G CGGCGUCC 5102 GGACGCCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GAGCACCA 12995
501 GUGCUCGC G GCGUCCAC 5363 GUGGACGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCGAGCAC 12996
502 UGCUCGCG G CGUCCACU 5103 AGUGGACG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGCGAGCA 12997
504 CUCGCGGC G UCCACUGC 5104 GCAGUGGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCCGCGAG 12998
511 CGUCCACU G CGCCCGCU 5105 AGCGGGCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGUGGACG 12999
513 UCCACUGC G CCCGCUGC 5106 GCAGCGGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCAGUGGA 13000
517 CUGCGCCC G CUGCCCUC 5107 GAGGGCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGGCGCAG 13001
520 CGCCCGCU G CCCUCGGU 5108 ACCGAGGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCGGGCG 13002
526 CUGCCCUC G GUCUUCUA 5364 UAGAAGAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GAGGGCAG 13003
527 UGCCCUCG G UCUUCUAC 5109 GUAGAAGA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGAGGGCA 13004
538 UUCUACAU G CUGGUGUG 5110 CACACCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUGUAGAA 13005
541 UACAUGCU G GUGUGUGG 5365 CCACACAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCAUGUA 13006
542 ACAUGCUG G UGUGUGGC 5111 GCCACACA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGCAUGU 13007
544 AUGCUGGU G UGUGGCCU 5112 AGGCCACA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACCAGCAU 13008
546 GCUGGUGU G UGGCCUGA 5113 UCAGGCCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACACCAGC 13009
548 UGGUGUGU G GCCUGACG 5366 CGUCAGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACACACCA 13010
549 GGUGUGUG G CCUGACGG 5114 CCGUCAGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CACACACC 13011
553 UGUGGCCU G ACGGUCAC 5367 GUGACCGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGCCACA 13012
556 GGCCUGAC G GUCACCGA 5368 UCGGUGAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GUCAGGCC 13013
557 GCCUGACG G UCACCGAC 5115 GUCGGUGA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGUCAGGC 13014
563 CGGUCACC G ACUUGCUG 5369 CAGCAAGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGUGACCG 13015
568 ACCGACUU G CUGGGCAA 5116 UUGCCCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAGUCGGU 13016
571 GACUUGCU G GGCAAGUG 5370 CACUUGCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCAAGUC 13017
572 ACUUGCUG G GCAAGUGC 5371 GCACUUGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGCAAGU 13018
573 CUUGCUGG G CAAGUGCC 5117 GGCACUUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCAGCAAG 13019
577 CUGGGCAA G UGCCUCCU 5118 AGGAGGCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUGCCCAG 13020
579 GGGCAAGU G CCUCCUAA 5119 UUAGGAGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACUUGCCC 13021
588 CCUCCUAA G CCCGGUGG 5120 CCACCGGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUAGGAGG 13022
592 CUAAGCCC G GUGGUGCU 5372 AGCACCAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGGCUUAG 13023
593 UAAGCCCG G UGGUGCUG 5121 CAGCACCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGGGCUUA 13024
595 AGCCCGGU G GUGCUGGC 5373 GCCAGCAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACCGGGCU 13025
596 GCCCGGUG G UGCUGGCU 5122 AGCCAGCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CACCGGGC 13026
598 CCGGUGGU G CUGGCUGC 5123 GCAGCCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACCACCGG 13027
601 GUGGUGCU G GCUGCCUA 5374 UAGGCAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCACCAC 13028
602 UGGUGCUG G CUGCCUAC 5124 GUAGGCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGCACCA 13029
Figure imgf000286_0001
605 UGCUGGCU G CCUACGCU 5125 AGCGUAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCCAGCA 13030
611 CUGCCUAC G CUCAGAAC 5126 GUUCUGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GUAGGCAG 13031
616 UACGCUCA G AACCGGAG 5375 CUCCGGUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGAGCGUA 13032
621 UCAGAACC G GAGUCUGC 5376 GCAGACUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGUUCUGA 13033
622 CAGAACCG G AGUCUGCG 5377 CGCAGACU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGGUUCUG 13034
624 GAACCGGA G UCUGCGGG 5127 CCCGCAGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCGGUUC 13035
628 CGGAGUCU G CGGGUGCU 5128 AGCACCCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGACUCCG 13036
630 GAGUCUGC G GGUGCUUG 5378 CAAGCACC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCAGACUC 13037
631 AGUCUGCG G GUGCUUGC 5379 GCAAGCAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGCAGACU 13038
632 GUCUGCGG G UGCUUGCG 5129 CGCAAGCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCGCAGAC 13039
634 CUGCGGGU G CUUGCGCC 5130 GGCGCAAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACCCGCAG 13040
638 GGGUGCUU G CGCCCGCA 5131 UGCGGGCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAGCACCC 13041
640 GUGCUUGC G CCCGCAUU 5132 AAUGCGGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCAAGCAC 13042
644 UUGCGCCC G CAUUGGAC 5133 GUCCAAUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGGCGCAA 13043
649 CCCGCAUU G GACAACUC 5380 GAGUUGUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAUGCGGG 13044
650 CCGCAUUG G ACAACUCG 5381 CGAGUUGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAAUGCGG 13045
658 GACAACUC G UUGUGCCA 5134 UGGCACAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GAGUUGUC 13046
661 AACUCGUU G UGCCAAGC 5135 GCUUGGCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AACGAGUU 13047
663 CUCGUUGU G CCAAGCCU 5136 AGGCUUGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACAACGAG 13048
668 UGUGCCAA G CCUUCGCC 5137 GGCGAAGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUGGCACA 13049
674 AAGCCUUC G CCUUCUUC 5138 GAAGAAGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GAAGGCUU 13050
685 UUCUUCAU G UCCUUCUU 5139 AAGAAGGA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUGAAGAA 13051
695 CCUUCUUU G GGCUCUCC 5382 GGAGAGCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAAGAAGG 13052
696 CUUCUUUG G GCUCUCCU 5383 AGGAGAGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAAAGAAG 13053
697 UUCUUUGG G CUCUCCUC 5140 GAGGAGAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCAAAGAA 13054
706 CUCUCCUC G ACACUGCA 5384 UGCAGUGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GAGGAGAG 13055
712 UCGACACU G CAACUCCU 5141 AGGAGUUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGUGUCGA 13056
721 CAACUCCU G GCCAUGGC 5385 GCCAUGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGAGUUG 13057
722 AACUCCUG G CCAUGGCA 5142 UGCCAUGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGGAGUU 13058
727 CUGGCCAU G GCACUGGA 5386 UCCAGUGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUGGCCAG 13059
728 UGGCCAUG G CACUGGAG 5143 CUCCAGUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAUGGCCA 13060
733 AUGGCACU G GAGUGCUG 5387 CAGCACUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGUGCCAU 13061
734 UGGCACUG G AGUGCUGG 5388 CCAGCACU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGUGCCA 13062
736 GCACUGGA G UGCUGGCU 5144 AGCCAGCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCAGUGC 13063
738 ACUGGAGU G CUGGCUCU 5145 AGAGCCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACUCCAGU 13064
741 GGAGUGCU G GCUCUCCC 5389 GGGAGAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCACUCC 13065
742 GAGUGCUG G CUCUCCCU 5146 AGGGAGAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGCACUC 13066
Figure imgf000287_0001
752 UCUCCCUA G GGCACCCU 5390 AGGGUGCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UAGGGAGA 13067
753 CUCCCUAG G GCACCCUU 5391 AAGGGUGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUAGGGAG 13068
754 UCCCUAGG G CACCCUUU 5147 AAAGGGUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCUAGGGA 13069
771 CUUCUACC G ACGGCACA 5392 UGUGCCGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGUAGAAG 13070
774 CUACCGAC G GCACAUCA 5393 UGAUGUGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GUCGGUAG 13071
775 UACCGACG G CACAUCAC 5148 GUGAUGUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGUCGGUA 13072
787 AUCACCCU G CGCCUGGG 5149 CCCAGGCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGGUGAU 13073
789 CACCCUGC G CCUGGGCG 5150 CGCCCAGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCAGGGUG 13074
793 CUGCGCCU G GGCGCACU 5394 AGUGCGCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGCGCAG 13075
794 UGCGCCUG G GCGCACUG 5395 CAGUGCGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGGCGCA 13076
795 GCGCCUGG G CGCACUGG 5151 CCAGUGCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCAGGCGC 13077
797 GCCUGGGC G CACUGGUG 5152 CACCAGUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCCCAGGC 13078
802 GGCGCACU G GUGGCCCC 5396 GGGGCCAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGUGCGCC 13079
803 GCGCACUG G UGGCCCCG 5153 CGGGGCCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGUGCGC 13080
805 GCACUGGU G GCCCCGGU 5397 ACCGGGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACCAGUGC 13081
806 CACUGGUG G CCCCGGUG 5154 CACCGGGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CACCAGUG 13082
811 GUGGCCCC G GUGGUGAG 5398 CUCACCAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGGGCCAC 13083
812 UGGCCCCG G UGGUGAGC 5155 GCUCACCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGGGGCCA 13084
814 GCCCCGGU G GUGAGCGC 5399 GCGCUCAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACCGGGGC 13085
815 CCCCGGUG G UGAGCGCC 5156 GGCGCUCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CACCGGGG 13086
817 CCGGUGGU G AGCGCCUU 5400 AAGGCGCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACCACCGG 13087
819 GGUGGUGA G CGCCUUCU 5157 AGAAGGCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCACCACC 13088
821 UGGUGAGC G CCUUCUCC 5158 GGAGAAGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCUCACCA 13089
832 UUCUCCCU G GCUUUCUG 5401 CAGAAAGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGGAGAA 13090
833 UCUCCCUG G CUUUCUGC 5159 GCAGAAAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGGGAGA 13091
840 GGCUUUCU G CGCGCUAC 5160 GUAGCGCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGAAAGCC 13092
842 CUUUCUGC G CGCUACCU 5161 AGGUAGCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCAGAAAG 13093
844 UUCUGCGC G CUACCUUU 5162 AAAGGUAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCGCAGAA 13094
856 CCUUUCAU G GGCUUCGG 5402 CCGAAGCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUGAAAGG 13095
857 CUUUCAUG G GCUUCGGG 5403 CCCGAAGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAUGAAAG 13096
858 UUUCAUGG G CUUCGGGA 5163 UCCCGAAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCAUGAAA 13097
863 UGGGCUUC G GGAAGUUC 5404 GAACUUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GAAGCCCA 13098
864 GGGCUUCG G GAAGUUCG 5405 CGAACUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGAAGCCC 13099
865 GGCUUCGG G AAGUUCGU 5406 ACGAACUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCGAAGCC 13100
868 UUCGGGAA G UUCGUGCA 5164 UGCACGAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCCCGAA 13101
872 GGAAGUUC G UGCAGUAC 5165 GUACUGCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GAACUUCC 13102
874 AAGUUCGU G CAGUACUG 5166 CAGUACUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACGAACUU 13103
Figure imgf000288_0001
877 UUCGUGCA G UACUGCCC 5167 GGGCAGUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCACGAA 13104
882 GCAGUACU G CCCCGGCA 5168 UGCCGGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGUACUGC 13105
887 ACUGCCCC G GCACCUGG 5407 CCAGGUGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGGGCAGU 13106
888 CUGCCCCG G CACCUGGU 5169 ACCAGGUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGGGGCAG 13107
894 CGGCACCU G GUGCUUUA 5408 UAAAGCAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGUGCCG 13108
895 GGCACCUG G UGCUUUAU 5170 AUAAAGCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGGUGCC 13109
897 CACCUGGU G CUUUAUCC 5171 GGAUAAAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACCAGGUG 13110
907 UUUAUCCA G AUGGUCCA 5409 UGGACCAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGAUAAA 13111
910 AUCCAGAU G GUCCACGA 5410 UCGUGGAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUCUGGAU 13112
911 UCCAGAUG G UCCACGAG 5172 CUCGUGGA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAUCUGGA 13113
917 UGGUCCAC G AGGAGGGC 5411 GCCCUCCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GUGGACCA 13114
919 GUCCACGA G GAGGGCUC 5412 GAGCCCUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCGUGGAC 13115
920 UCCACGAG G AGGGCUCG 5413 CGAGCCCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUCGUGGA 13116
922 CACGAGGA G GGCUCGCU 5414 AGCGAGCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCUCGUG 13117
923 ACGAGGAG G GCUCGCUG 5415 CAGCGAGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUCCUCGU 13118
924 CGAGGAGG G CUCGCUGU 5173 ACAGCGAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCUCCUCG 13119
928 GAGGGCUC G CUGUCGGU 5174 ACCGACAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GAGCCCUC 13120
931 GGCUCGCU G UCGGUGCU 5175 AGCACCGA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCGAGCC 13121
934 UCGCUGUC G GUGCUGGG 5416 CCCAGCAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GACAGCGA 13122
935 CGCUGUCG G UGCUGGGG 5176 CCCCAGCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGACAGCG 13123
937 CUGUCGGU G CUGGGGUA 5177 UACCCCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACCGACAG 13124
940 UCGGUGCU G GGGUACUC 5417 GAGUACCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCACCGA 13125
941 CGGUGCUG G GGUACUCU 5418 AGAGUACC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGCACCG 13126
942 GGUGCUGG G GUACUCUG 5419 CAGAGUAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCAGCACC 13127
943 GUGCUGGG G UACUCUGU 5178 ACAGAGUA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCCAGCAC 13128
950 GGUACUCU G UGCUCUAC 5179 GUAGAGCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGAGUACC 13129
952 UACUCUGU G CUCUACUC 5180 GAGUAGAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACAGAGUA 13130
963 CUACUCCA G CCUCAUGG 5181 CCAUGAGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGAGUAG 13131
970 AGCCUCAU G GCGCUGCU 5420 AGGAGCGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUGAGGCU 13132
971 GCCUCAUG G CGCUGCUG 5182 CAGCAGCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAUGAGGC 13133
973 CUCAUGGC G CUGCUGGU 5183 ACCAGCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCCAUGAG 13134
976 AUGGCGCU G CUGGUCCU 5184 AGGACCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCGCCAU 13135
979 GCGCUGCU G GUCCUCGC 5421 GCGAGGAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCAGCGC 13136
980 CGCUGCUG G UCCUCGCC 5185 GGCGAGGA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGCAGCG 13137
986 UGGUCCUC G CCACCGUG 5186 CACGGUGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GAGGACCA 13138
992 UCGCCACC G UGCUGUGC 5187 GCACAGCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGUGGCGA 13139
994 GCCACCGU G CUGUGCAA 5188 UUGCACAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACGGUGGC 13140
Figure imgf000289_0001
997 ACCGUGCU G UGCAACCU 5189 AGGUUGCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCACGGU 13141
999 CGUGCUGU G CAACCUCG 5190 CGAGGUUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACAGCACG 13142
1007 GCAACCUC G GCGCCAUG 5422 CAUGGCGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GAGGUUGC 13143
1008 CAACCUCG G CGCCAUGC 5191 GCAUGGCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGAGGUUG 13144
1010 ACCUCGGC G CCAUGCGC 5192 GCGCAUGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCCGAGGU 13145
1015 GGCGCCAU G CGCAACCU 5193 AGGUUGCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUGGCGCC 13146
1017 CGCCAUGC G CAACCUCU 5194 AGAGGUUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCAUGGCG 13147
1028 ACCUCUAU G CGAUGCAC 5195 GUGCAUCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUAGAGGU 13148
1030 CUCUAUGC G AUGCACCG 5423 CGGUGCAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCAUAGAG 13149
1033 UAUGCGAU G CACCGGCG 5196 CGCCGGUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUCGCAUA 13150
1038 GAUGCACC G GCGGCUGC 5424 GCAGCCGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGUGCAUC 13151
1039 AUGCACCG G CGGCUGCA 5197 UGCAGCCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGGUGCAU 13152
1041 GCACCGGC G GCUGCAGC 5425 GCUGCAGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCCGGUGC 13153
1042 CACCGGCG G CUGCAGCG 5198 CGCUGCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGCCGGUG 13154
1045 CGGCGGCU G CAGCGGCA 5199 UGCCGCUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCCGCCG 13155
1048 CGGCUGCA G CGGCACCC 5200 GGGUGCCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGCAGCCG 13156
1050 GCUGCAGC G GCACCCGC 5426 GCGGGUGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCUGCAGC 13157
1051 CUGCAGCG G CACCCGCG 5201 CGCGGGUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGCUGCAG 13158
1057 CGGCACCC G CGCUCCUG 5202 CAGGAGCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGGUGCCG 13159
1059 GCACCCGC G CUCCUGCA 5203 UGCAGGAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCGGGUGC 13160
1065 GCGCUCCU G CACCAGGG 5204 CCCUGGUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGAGCGC 13161
1071 CUGCACCA G GGACUGUG 5427 CACAGUCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGUGCAG 13162
1072 UGCACCAG G GACUGUGC 5428 GCACAGUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUGGUGCA 13163
1073 GCACCAGG G ACUGUGCC 5429 GGCACAGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCUGGUGC 13164
1077 CAGGGACU G UGCCGAGC 5205 GCUCGGCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGUCCCUG 13165
1079 GGGACUGU G CCGAGCCG 5206 CGGCUCGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACAGUCCC 13166
1082 ACUGUGCC G AGCCGCGC 5430 GCGCGGCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGCACAGU 13167
1084 UGUGCCGA G CCGCGCGC 5207 GCGCGCGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCGGCACA 13168
1087 GCCGAGCC G CGCGCGGA 5208 UCCGCGCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGCUCGGC 13169
1089 CGAGCCGC G CGCGGACG 5209 CGUCCGCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCGGCUCG 13170
1091 AGCCGCGC G CGGACGGG 5210 CCCGUCCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCGCGGCU 13171
1093 CCGCGCGC G GACGGGAG 5431 CUCCCGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCGCGCGG 13172
1094 CGCGCGCG G ACGGGAGG 5432 CCUCCCGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGCGCGCG 13173
1097 GCGCGGAC G GGAGGGAA 5433 UUCCCUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GUCCGCGC 13174
1098 CGCGGACG G GAGGGAAG 5434 CUUCCCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGUCCGCG 13175
1099 GCGGACGG G AGGGAAGC 5435 GCUUCCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCGUCCGC 13176
1101 GGACGGGA G GGAAGCGU 5436 ACGCUUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCCGUCC 13177
Figure imgf000290_0001
1102 GACGGGAG G GAAGCGUC 5437 GACGCUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCCCGUC 13178
1103 ACGGGAGG G AAGCGUCC 5438 GGACGCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCUCCCGU 13179
1106 GGAGGGAA G CGUCCCCU 5211 AGGGGACG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCCCUCC 13180
1108 AGGGAAGC G UCCCCUCA 5212 UGAGGGGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCUUCCCU 13181
1117 UCCCCUCA G CCCCUGGA 5213 UCCAGGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGAGGGGA 13182
1123 CAGCCCCU G GAGGAGCU 5439 AGCUCCUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGGGCUG 13183
1124 AGCCCCUG G AGGAGCUG 5440 CAGCUCCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGGGGCU 13184
1126 CCCCUGGA G GAGCUGGA 5441 UCCAGCUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCAGGGG 13185
1127 CCCUGGAG G AGCUGGAU 5442 AUCCAGCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUCCAGGG 13186
1129 CUGGAGGA G CUGGAUCA 5214 UGAUCCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCUCCAG 13187
1132 GAGGAGCU G GAUCACCU 5443 AGGUGAUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCUCCUC 13188
1133 AGGAGCUG G AUCACCUC 5444 GAGGUGAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGCUCCU 13189
1144 CACCUCCU G CUGCUGGC 5215 GCCAGCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGAGGUG 13190
1147 CUCCUGCU G CUGGCGCU 5216 AGCGCCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCAGGAG 13191
1150 CUGCUGCU G GCGCUGAU 5445 AUCAGCGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCAGCAG 13192
1151 UGCUGCUG G CGCUGAUG 5217 CAUCAGCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGCAGCA 13193
1153 CUGCUGGC G CUGAUGAC 5218 GUCAUCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCCAGCAG 13194
1156 CUGGCGCU G AUGACCGU 5446 ACGGUCAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCGCCAG 13195
1159 GCGCUGAU G ACCGUGCU 5447 AGCACGGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUCAGCGC 13196
1163 UGAUGACC G UGCUCUUC 5219 GAAGAGCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGUCAUCA 13197
1165 AUGACCGU G CUCUUCAC 5220 GUGAAGAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACGGUCAU 13198
1177 UUCACUAU G UGUUCUCU 5221 AGAGAACA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUAGUGAA 13199
1179 CACUAUGU G UUCUCUGC 5222 GCAGAGAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACAUAGUG 13200
1186 UGUUCUCU G CCCGUAAU 5223 AUUACGGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGAGAACA 13201
1190 CUCUGCCC G UAAUUUAU 5224 AUAAAUUA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGGCAGAG 13202
1200 AAUUUAUC G CGCUUACU 5225 AGUAAGCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GAUAAAUU 13203
1202 UUUAUCGC G CUUACUAU 5226 AUAGUAAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCGAUAAA 13204
1211 CUUACUAU G GAGCAUUU 5448 AAAUGCUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUAGUAAG 13205
1212 UUACUAUG G AGCAUUUA 5449 UAAAUGCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAUAGUAA 13206
1214 ACUAUGGA G CAUUUAAG 5227 CUUAAAUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCAUAGU 13207
1222 GCAUUUAA G GAUGUCAA 5450 UUGACAUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUAAAUGC 13208
1223 CAUUUAAG G AUGUCAAG 5451 CUUGACAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUAAAUG 13209
1226 UUAAGGAU G UCAAGGAG 5228 CUCCUUGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUCCUUAA 13210
1231 GAUGUCAA G GAGAAAAA 5452 UUUUUCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGACAUC 13211
1232 AUGUCAAG G AGAAAAAC 5453 GUUUUUCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUGACAU 13212
1234 GUCAAGGA G AAAAACAG 5454 CUGUUUUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCUUGAC 13213
1242 GAAAAACA G GACCUCUG 5455 CAGAGGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUUUUUC 13214
Figure imgf000291_0001
1243 AAAAACAG G ACCUCUGA 5456 UCAGAGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGUUUUU 13215
1250 GGACCUCU G AAGAAGCA 5457 UGCUUCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAGGUCC 13216
1253 CCUCUGAA G AAGCAGAA 5458 UUCUGCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCAGAGG 13217
1256 CUGAAGAA G CAGAAGAC 5229 GUCUUCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCUUCAG 13218
1259 AAGAAGCA G AAGACCUC 5459 GAGGUCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCUUCUU 13219
1262 AAGCAGAA G ACCUCCGA 5460 UCGGAGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCUGCUU 13220
1269 AGACCUCC G AGCCUUGC 5461 GCAAGGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGAGGUCU 13221
1271 ACCUCCGA G CCUUGCGA 5230 UCGCAAGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCGGAGGU 13222
1276 CGAGCCUU G CGAUUUCU 5231 AGAAAUCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAGGCUCG 13223
1278 AGCCUUGC G AUUUCUAU 5462 AUAGAAAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCAAGGCU 13224
1289 UUCUAUCU G UGAUUUCA 5232 UGAAAUCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGAUAGAA 13225
1291 CUAUCUGU G AUUUCAAU 5463 AUUGAAAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACAGAUAG 13226
1301 UUUCAAUU G UGGACCCU 5233 AGGGUCCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAUUGAAA 13227
1303 UCAAUUGU G GACCCUUG 5464 CAAGGGUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACAAUUGA 13228
1304 CAAUUGUG G ACCCUUGG 5465 CCAAGGGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CACAAUUG 13229
1311 GGACCCUU G GAUUUUUA 5466 UAAAAAUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAGGGUCC 13230
1312 GACCCUUG G AUUUUUAU 5467 AUAAAAAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAAGGGUC 13231
1329 CAUUUUCA G AUCUCCAG 5468 CUGGAGAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGAAAAUG 13232
1337 GAUCUCCA G UAUUUCGG 5234 CCGAAAUA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGAGAUC 13233
1344 AGUAUUUC G GAUAUUUU 5469 AAAAUAUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GAAAUACU 13234
1345 GUAUUUCG G AUAUUUUU 5470 AAAAAUAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGAAAUAC 13235
1360 UUUCACAA G AUUUUCAU 5471 AUGAAAAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUGUGAAA 13236
1371 UUUCAUUA G ACCUCUUA 5472 UAAGAGGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UAAUGAAA 13237
1380 ACCUCUUA G GUACAGGA 5473 UCCUGUAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UAAGAGGU 13238
1381 CCUCUUAG G UACAGGAG 5235 CUCCUGUA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUAAGAGG 13239
1386 UAGGUACA G GAGCCGGU 5474 ACCGGCUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGUACCUA 13240
1387 AGGUACAG G AGCCGGUG 5475 CACCGGCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUGUACCU 13241
1389 GUACAGGA G CCGGUGCA 5236 UGCACCGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCUGUAC 13242
1392 CAGGAGCC G GUGCAGCA 5476 UGCUGCAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGCUCCUG 13243
1393 AGGAGCCG G UGCAGCAA 5237 UUGCUGCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGGCUCCU 13244
1395 GAGCCGGU G CAGCAAUU 5238 AAUUGCUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACCGGCUC 13245
1398 CCGGUGCA G CAAUUCCA 5239 UGGAAUUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCACCGG 13246
1414 ACUAACAU G GAAUCCAG 5477 CUGGAUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUGUUAGU 13247
1415 CUAACAUG G AAUCCAGU 5478 ACUGGAUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUGUUAG 13248
1422 GGAAUCCA G UCUGUGAC 5240 GUCACAGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGAUUCC 13249
1426 UCCAGUCU G UGACAGUG 5241 CACUGUCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGACUGGA 13250
1428 CAGUCUGU G ACAGUGUU 5479 AACACUGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACAGACUG 13251
Figure imgf000292_0001
1432 CUGUGACA G UGUUUUUC 5242 GAAAAACA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUCACAG 13252
1434 GUGACAGU G UUUUUCAC 5243 GUGAAAAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACUGUCAC 13253
1446 UUCACUCU G UGGUAAGC 5244 GCUUACCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAGUGAA 13254
1448 CACUCUGU G GUAAGCUG 5480 CAGCUUAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACAGAGUG 13255
1449 ACUCUGUG G UAAGCUGA 5245 UCAGCUUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CACAGAGU 13256
1453 UGUGGUAA G CUGAGGAA 5246 UUCCUCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUACCACA 13257
1456 GGUAAGCU G AGGAAUAU 5481 AUAUUCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCUUACC 13258
1458 UAAGCUGA G GAAUAUGU 5482 ACAUAUUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCAGCUUA 13259
1459 AAGCUGAG G AAUAUGUC 5483 GACAUAUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUCAGCUU 13260
1465 AGGAAUAU G UCACAUUU 5247 AAAUGUGA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUAUUCCU 13261
1477 CAUUUUCA G UCAAAGAA 5248 UUCUUUGA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGAAAAUG 13262
Input Sequence = PTGDR_composit . Cut Site = G/ .
Arm Length = 8. Core Sequence = GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG
PTGDR_composit (1 to 993 of HSU31332 (PTGDR 5') + 1 to 495 of HSU31099 (PTGDR 3'); 1488 nt)

Claims

CLAIMS What we claim is:
1. A nucleic acid molecule that down regulates expression or inhibits function of a receptor for a neurite growth inhibitor.
2. A nucleic acid molecule of claim 1, wherein the receptor is a NOGO receptor.
3. The nucleic acid of claim 1, wherein said nucleic acid molecule is adapted for use to treat conditions selected from the group consisting of CNS injury, spinal cord injury, and cerebrovascular accident.
4. The nucleic acid molecule of claim 1 or claim 2, wherein said nucleic acid molecule is an enzymatic nucleic acid molecule having at least one binding arm.
5. The nucleic acid molecule of claim 4, wherein said enzymatic nucleic acid molecule has an endonuclease activity to cleave RNA encoded by a NOGO receptor gene.
6. The nucleic acid of claim 4, wherein the at least one binding arm of the enzymatic nucleic acid molecule comprises a sequence complementary to a sequence selected from the group consisting of SEQ ID NOs. 1-1023.
7. An enzymatic nucleic acid molecule comprising a sequence selected from the group consisting of SEQ ID NOs. 5484-7055.
8. The nucleic acid molecule of claim 1, wherein said nucleic acid molecule is an antisense nucleic acid molecule.
9. An antisense nucleic acid molecule comprising a sequence complementary to a sequence selected from the group consisting of SEQ ID NOs. 1-1023.
10. The enzymatic nucleic acid molecule of claim 4, wherein said enzymatic nucleic acid molecule is in a hammerhead (HH) motif.
11. The enzymatic nucleic acid molecule of claim 4, wherein said enzymatic nucleic acid molecule is in a hairpin, hepatitis Delta virus, group I intron, VS nucleic acid, amberzyme, zinzyme or RNAse P nucleic acid motif.
12. The enzymatic nucleic acid molecule of claim 11, wherein said zinzyme motif comprises a sequence selected from the group consisting of SEQ ID NOs. 6030- 6272.
13. The enzymatic nucleic acid molecule of claim 11, wherein said amberzyme motif comprises a sequence selected from the group consisting of SEQ ID NOs. 6630- 7055.
14. The enzymatic nucleic acid molecule of claim 4, wherein said enzymatic nucleic acid molecule is in a NCH motif.
15. The enzymatic nucleic acid molecule of claim 4, wherein said enzymatic nucleic acid molecule is in a G-cleaver motif.
16. The enzymatic nucleic acid molecule of claim 4, wherein said enzymatic nucleic acid molecule is a DNAzyme.
17. The nucleic acid molecule of claim 2, wherein said nucleic acid molecule comprises between 12 and 100 bases complementary to RNA encoded by a NOGO receptor gene.
18. The nucleic acid molecule of claim 2, wherein said nucleic acid molecule comprises between 14 and 24 bases complementary to the RNA encoded by a NOGO receptor gene.
19. The nucleic acid molecule of claim 1, wherein said nucleic acid molecule is chemically synthesized.
20. The nucleic acid molecule of claim 1, wherein said nucleic acid molecule comprises at least one 2 '-sugar modification.
21. The nucleic acid molecule of claim 1, wherein said nucleic acid molecule comprises at least one nucleic acid base modification.
22. The nucleic acid molecule of claim 1, wherein said nucleic acid molecule comprises at least one phosphate backbone modification.
23. A mammalian cell comprising the nucleic acid molecule of claim 1.
24. The mammalian cell of claim 23, wherein said mammalian cell is a human cell.
25. A method of reducing NOGO receptor activity in a cell, comprising the step of contacting said cell with the nucleic acid molecule of claim 2, under conditions suitable for said inhibition.
26. A method of treatment of a patient having a condition associated with levels of a NOGO receptor, comprising contacting cells of said patient with the nucleic acid molecule of claim 2, under conditions suitable for said treatment.
27. The method of claim 26 further comprising the use of one or more drug therapies under conditions suitable for said treatment.
28. A method of cleaving RNA encoded by a NOGO receptor gene comprising contacting the nucleic acid molecule of claim 2 with said RNA under conditions suitable for the cleavage of said RNA.
29. The method of claim 28, wherein said cleavage is carried out in the presence of a divalent cation.
30. The method of claim 29, wherein said divalent cation is Mg2+.
31. The nucleic acid molecule of claim 1, wherein said nucleic acid comprises a cap structure, wherein the cap structure is at the 5'-end, 3'-end, or both the 5'-end and the 3 '-end.
32. The enzymatic nucleic acid molecule of claim 10, wherein said hammerhead motif comprises a sequence selected from the group consisting of SEQ ID NOs.
5484-5583.
33. The enzymatic nucleic acid molecule of claim 14, wherein said NCH motif comprises a sequence selected from the group consisting of SEQ ID NOs. 5584- 6029.
34. The enzymatic nucleic acid molecule of claim 16, wherein said DNAzyme comprises a sequence selected from the group consisting of SEQ ID NOs. 6273- 6629.
35. The method of claim 25, wherein said nucleic acid molecule is in a hammerhead motif.
36. The method of claim 25, wherein said nucleic acid molecule is a DNAzyme.
37. An expression vector comprising at least one nucleic acid molecule of claim 1 in a manner that allows expression ofthe nucleic acid molecule.
38. A mammalian cell comprising an expression vector of claim 37.
39. The mammalian cell of claim 38, wherein said mammalian cell is a human cell.
40. The expression vector of claim 37, wherein said expression vector encodes a nucleic acid molecule having a hammerhead motif.
41. The expression vector of claim 37, wherein said expression vector further comprises a sequence for an antisense nucleic acid molecule complementary to RNA encoded by a NOGO receptor gene.
42. The expression vector of claim 37, wherein said expression vector comprises a two or more of said nucleic acid molecules, which can be the same or different.
43. The expression vector of claim 42, wherein said expression vector comprises a sequence encoding an antisense nucleic acid molecule complementary to RNA encoded by a NOGO receptor gene.
44. A method for treatment of conditions selected from the group consisting of CNS injury and cerebrovascular accident comprising the step of administering to a patient the nucleic acid molecule of claim 1 under conditions suitable for said treatment.
45. The method of claim 44, wherein said treatment of CNS injury is treatment of spinal cord injury.
46. A method for treatment of conditions selected from the group consisting of CNS injury and cerebrovascular accident comprising the step of administering to a patient the antisense nucleic acid molecule of claim 9 under conditions suitable for said treatment.
47. The method of claim 44, wherein said nucleic acid molecule is in a hammerhead motif.
48. The method of claim 44, wherein said method further comprises administering to said patient one or more other therapies.
49. The nucleic acid molecule of claim 1, wherein said nucleic acid molecule comprises at least five ribose residues, at least ten 2'-O-methyl modifications, and a 3'- end modification.
50. The nucleic acid molecule of claim 49, wherein said nucleic acid molecule further comprises phosphorothioate linkages on at least three of the 5' terminal nucleotides.
51. The nucleic acid molecule of claim 49, wherein said 3'- end modification is 3'-3' inverted abasic moiety.
52. The enzymatic nucleic acid molecule of claim 16, wherein said DNAzyme comprises at least ten 2'-O-methyl modifications and a 3 '-end modification.
53. The enzymatic nucleic acid molecule of claim 52, wherein said DNAzyme further comprises phosphorothioate linkages on at least three of the 5' terminal nucleotides.
54. The enzymatic nucleic acid molecule of claim 52, wherein said 3'- end modification is 3 '-3' inverted abasic moiety.
55. An enzymatic nucleic acid molecule that down regulates expression of a nucleic acid molecule encoding an DcappaB kinase (D K) subunit.
56. An enzymatic nucleic acid molecule that down regulates expression of a nucleic acid molecule encoding protein kinase PKR.
57. An enzymatic nucleic acid molecule comprising a sequence selected from the group consisting of SEQ ID NOs. 7056-11665.
58. An enzymatic nucleic acid molecule comprising at least one binding arm wherein one or more of said binding arms comprises a sequence complementary to a sequence selected from the group consisting of SEQ ID NOs. 1024-4414.
59. An antisense nucleic acid molecule comprising a sequence complementary to a sequence selected from the group consisting of SEQ ED NOs. 1024-4414.
60. The enzymatic nucleic acid molecule of any of claims 55-58, wherein said enzymatic nucleic acid molecule is adapted to treat cancer.
61. The antisense nucleic acid molecule of claim 59, wherein said antisense nucleic acid molecule is adapted to treat cancer.
62. The enzymatic nucleic acid molecule of any of claims 55-58, wherein said enzymatic nucleic acid molecule has an endonuclease activity to cleave RNA encoded by a IKK-gamma gene or PKR gene.
63. The enzymatic nucleic acid molecule of claim 55 or claim 56, wherein said enzymatic nucleic acid molecule is in an Inozyme configuration.
64. The enzymatic nucleic acid molecule of claim 55 or claim 56, wherein said enzymatic nucleic acid molecule is in a Zinzyme configuration.
65. The enzymatic nucleic acid molecule of claim 55 or claim 56, wherein said enzymatic nucleic acid molecule is in a G-cleaver configuration.
66. The enzymatic nucleic acid molecule of claim 55 or claim 56, wherein said enzymatic nucleic acid molecule is in an Amberzyme configuration.
67. The enzymatic nucleic acid molecule of claim 55 or claim 56, wherein said enzymatic nucleic acid molecule is in a DNAzyme configuration.
68. The enzymatic nucleic acid molecule of claim 55 or claim 56, wherein said enzymatic nucleic acid molecule is in a Hammerhead configuration.
69. The enzymatic nucleic acid molecule of claim 63, wherein said Inozyme comprises a sequence complementary to a sequence selected from the group consisting of SEQ ID NOs. 1218-1721 and 3051-3549.
70. The enzymatic nucleic acid molecule of claim 63, wherein said Inozyme comprises a sequence selected from the group consisting of SEQ ID NOs. 7250- 7753 and 9701-10199.
71. The enzymatic nucleic acid molecule of claim 64, wherein said Zinzyme comprises a sequence complementary to a sequence selected from the group consisting of SEQ ID NOs. 1722-1998 and 3550-3768.
72. The enzymatic nucleic acid molecule of claim 64, wherein said Zinzyme comprises a sequence selected from the group consisting of SEQ ID NOs 7754- 8030 and 10200-10418.
73. The enzymatic nucleic acid molecule of claim 66, wherein said Amberzyme comprises a sequence selected from the group consisting of SEQ ID NOs 8441- 9069 and 11001-11547.
74. The enzymatic nucleic acid molecule of claim 67, wherein said DNAzyme comprises a sequence selected from the group consisting of SEQ ED NOs 8031- 8440 and 10419-11000.
75. The enzymatic nucleic acid molecule of claim 68, wherein said Hammerhead comprises a sequence complementary to a sequence selected from the group consisting of SEQ ID NOs. 1024-1217 and 2420-3050.
76. The enzymatic nucleic acid molecule of claim 68, wherein said Hammerhead comprises a sequence selected from the group consisting of SEQ ID NOs 7056- 7249 and 9070-9700.
77. The enzymatic nucleic acid molecule of any of claims 55-58, wherein said enzymatic nucleic acid molecule comprises between 12 and 100 bases complementary to RNA encoded by an IKK-gamma gene or PKR gene.
78. The enzymatic nucleic acid molecule of any of claims 55-58, wherein said enzymatic nucleic acid molecule comprises between 14 and 24 bases complementary to RNA encoded by an IKK-gamma gene or PKR gene.
79. The enzymatic nucleic acid molecule of any of claims 55-58 wherein said enzymatic nucleic acid molecule is chemically synthesized.
80. The antisense nucleic acid molecule of claim 59, wherein said antisense nucleic acid molecule is chemically synthesized.
81. The enzymatic nucleic acid molecule of any of claims 55-58, wherein said enzymatic nucleic acid molecule comprises at least one 2 '-sugar modification.
82. The antisense nucleic acid molecule of claim 59, wherein said antisense nucleic acid molecule comprises at least one 2 '-sugar modification.
83. The enzymatic nucleic acid molecule of any of claims 55-58, wherein said enzymatic nucleic acid molecule comprises at least one nucleic acid base modification.
84. The antisense nucleic acid molecule of claim 59, wherein said antisense nucleic acid molecule comprises at least one nucleic acid base modification.
85. The enzymatic nucleic acid molecule of any of claims 55-58, wherein said enzymatic nucleic acid molecule comprises at least one phosphate backbone modification.
86. The antisense nucleic acid molecule of claim 59, wherein said antisense nucleic acid molecule comprises at least one phosphate backbone modification.
87. A mammalian cell including the enzymatic nucleic acid molecule of any of claims
55-58.
88. The mammalian cell of claim 87, wherein said mammalian cell is a human cell.
89. A method of down-regulating PKR activity in a cell, comprising contacting said cell with the enzymatic nucleic acid molecule of claim 56, under conditions suitable for down-regulating of PKR activity.
90. A method of treatment of a patient having a condition associated with the level of PKR, comprising contacting cells of said patient with the enzymatic nucleic acid molecule of any of claims 55-59, under conditions suitable for said treatment.
91. A method of down-regulating IKK-gamma activity in a cell, comprising contacting said cell with the enzymatic nucleic acid molecule of any of claims 55- 59, under conditions suitable for down-regulating of EKK-gamma activity.
92. A method of treatment of a patient having a condition associated with the level of IKK-gamma, comprising contacting cells of said patient with the enzymatic nucleic acid molecule of any of claims 55-59, under conditions suitable for said treatment.
93. The method of claim 89 further comprising the use of one or more drug therapies under conditions suitable for said treatment.
94. The method of claim 90 further comprising the use of one or more drug therapies under conditions suitable for said treatment.
95. The method of claim 91 further comprising the use of one or more drug therapies under conditions suitable for said treatment.
96. The method of claim 92 further comprising the use of one or more drug therapies under conditions suitable for said treatment.
97. A method of cleaving RNA encoded by a PKR gene comprising contacting an enzymatic nucleic acid molecule of claim 56 with said RNA under conditions suitable for the cleavage.
98. A method of cleaving RNA encoded by an EKK-gamma gene comprising contacting an enzymatic nucleic acid molecule of claim 55 with said RNA under conditions suitable for the cleavage.
99. The method of claim 98, wherein said cleavage is carried out in the presence of a divalent cation.
100. The method of claim 99, wherein said cleavage is carried out in the presence of a divalent cation.
101. The method of claim 100, wherein said divalent cation is Mg2+.
102. The method of claim 101, wherein said divalent cation is Mg2+.
103. The enzymatic nucleic acid molecule of any of claims 55-58, wherein said enzymatic nucleic acid comprises a cap structure, wherein the cap structure is at the 5'-end,the 3 '-end, or both the 5 '-end and the 3 '-end.
104. The antisense nucleic acid molecule of claim 59, wherein said antisense nucleic acid comprises a cap structure, wherein the cap structure is at the 5'-end, the 3'- end, or both the 5 '-end and the 3 '-end.
105. The enzymatic nucleic acid molecule of claim 103, wherein the cap structure at the 5'-end, 3'-end, or both the 5'-end and the 3'-end comprises a 3',3'-linked or 5',5'-linked deoxyabasic ribose derivative.
106. The antisense nucleic acid molecule of claim 104, wherein the cap structure at the 5'-end, 3'-end, or both the 5'-end and the 3'-end comprises a 3',3'-linked or 5', 5'- linked deoxyabasic ribose derivative.
107. The method of claim 89, wherein said enzymatic nucleic acid molecule is in a Zinzyme configuration.
108. An expression vector comprising at least one enzymatic nucleic acid molecule of claim 55 or claim 56 in a manner that allows expression of the nucleic acid molecule.
109. A mammalian cell comprising the expression vector of claim 108.
110. The mammalian cell of claim 109, wherein said mammalian cell is a human cell.
111. The expression vector of claim 108, wherein said enzymatic nucleic acid molecule is in a hammerhead configuration. (DOES THIS MAKE SENSE?)
112. The expression vector of claim 108, wherein said expression vector further comprises a sequence for an antisense nucleic acid molecule complementary to RNA encoded by an IKK-gamma subunit gene or PKR gene.
113. The expression vector of claim 108, wherein said expression vector comprises a nucleic acid sequence encoding two or more of said enzymatic nucleic acid molecules, which can be the same or different.
114. The expression vector of claim 108, wherein said expression vector further comprises a sequence encoding an antisense nucleic acid molecule complementary to RNA encoded by an EKK-gamma gene or PKR gene.
115. A method for treatment of cancer comprising administering to a patient the enzymatic nucleic acid molecule of any of claims 55-58 under conditions suitable for said treatment.
116. The method of claim 115, wherein said cancer is breast cancer, lung cancer, prostate cancer, colorectal cancer, brain cancer, esophageal cancer, stomach cancer, bladder cancer, pancreatic cancer, cervical cancer, head and neck cancer, ovarian cancer, melanoma, lymphoma, glioma, or multidrug resistant cancer.
117. A method for treatment of cancer comprising administering to a patient the antisense nucleic acid molecule of claim 59 under conditions suitable for said treatment.
118. The method of claim 117, wherein said cancer is breast cancer, lung cancer, prostate cancer, colorectal cancer, brain cancer, esophageal cancer, stomach cancer, bladder cancer, pancreatic cancer, cervical cancer, head and neck cancer, ovarian cancer, melanoma, lymphoma, glioma, or multidrug resistant cancer.
119. The method of claim 115, wherein said enzymatic nucleic acid molecule is in a Zinzyme configuration.
120. The method of claim 115, wherein said method further comprises administering to said patient one or more other therapies.
121. The method of claim 117, wherein said method further comprises administering to said patient one or more other therapies.
122. The nucleic acid molecule of any of claims 55, 56, or 58, wherein said nucleic acid molecule comprises at least five ribose residues, at least ten 2'-O-methyl modifications, and a 3'- end modification.
123. The nucleic acid molecule of claim 122, wherein said nucleic acid molecule further comprises phosphorothioate linkages on at least three of the 5' terminal nucleotides.
124. The nucleic acid molecule of claim 122, wherein said 3'- end modification is a 3'- 3' inverted abasic moiety.
125. The method of claim 93 wherein said other drug therapies are monoclonal antibodies, EKK-gamma or PKR-specific inhibitors, chemotherapy, or radiation therapy.
126. The method of claim 125, wherein said chemotherapy is paclitaxel, docetaxel, cisplatin, methotrexate, cyclophosphamide, doxorubin, fluorouracil carboplatin, edatrexate, gemcitabine, or vinorelbine.
127. The method of claim 94 wherein said other drug therapies are monoclonal antibodies, EKK-gamma or PKR-specific inhibitors, chemotherapy, or radiation therapy.
128. The method of claim 127, wherein said chemotherapy is paclitaxel, docetaxel, cisplatin, methotrexate, cyclophosphamide, doxorubin, fluorouracil carboplatin, edatrexate, gemcitabine, or vinorelbine.
129. The method of claim 95 wherein said other drug therapies are monoclonal antibodies, EKK-gamma or PKR-specific inhibitors, chemotherapy, or radiation therapy.
130. The method of claim 129, wherein said chemotherapy is paclitaxel, docetaxel, cisplatin, methotrexate, cyclophosphamide, doxorubin, fluorouracil carboplatin, edatrexate, gemcitabine, or vinorelbine.
131. The method of claim 96 wherein said other drug therapies are monoclonal antibodies, EKK-gamma or PKR-specific inhibitors, chemotherapy, or radiation therapy.
132. The method of claim 131, wherein said chemotherapy is paclitaxel, docetaxel, cisplatin, methotrexate, cyclophosphamide, doxorubin, fluorouracil carboplatin, edatrexate, gemcitabine, or vinorelbine.
133. The method of claim 120, wherein said other therapies are monoclonal antibodies, IKK-gamma or PKR-specific inhibitors, chemotherapy, or radiation therapy.
134. The method of claim 133, wherein said chemotherapy is paclitaxel, docetaxel, cisplatin, methotrexate, cyclophosphamide, doxorubin, fluorouracil carboplatin, edatrexate, gemcitabine, or vinorelbine.
135. The method of claim 121, wherein said other therapies are monoclonal antibodies, EKK-gamma or PKR-specific inhibitors, chemotherapy, or radiation therapy.
136. The method of claim 135, wherein said chemotherapy is paclitaxel, docetaxel, cisplatin, methotrexate, cyclophosphamide, doxorubin, fluorouracil carboplatin, edatrexate, gemcitabine, or vinorelbine.
137. A method for treatment of an inflammatory disease comprising the step of administering to a patient the enzymatic nucleic acid molecule of any of claims 55-58 under conditions suitable for said treatment.
138. The method of claim 137, wherein said inflammatory disease is rheumatoid arthritis, restenosis, asthma, Crohn's disease, diabetes, obesity, autoimmune disease, lupus, multiple sclerosis, transplant/graft rejection, gene therapy applications, ischemia/reperfusion injury, glomerulonephritis, sepsis, allergic airway inflammation, inflammatory bowel disease, or infection.
139. A method for treatment of an inflammatory disease comprising the step of administering to a patient the antisense nucleic acid molecule of claim 59 under conditions suitable for said treatment.
140. The method of claim 139, wherein said inflammatory disease is rheumatoid arthritis, restenosis, asthma, Crohn's disease, diabetes, obesity, autoimmune disease, lupus, multiple sclerosis, transplant/graft rejection, gene therapy applications, ischemia/reperfusion injury (CNS and myocardial), glomerulonephritis, sepsis, allergic airway inflammation, inflammatory bowel disease, or infection.
141. The method of claim 137, wherein said enzymatic nucleic acid molecule is in a Zinzyme configuration.
142. The method of claim 137, wherein said method further comprises administering to said patient one or more other therapies.
143. The method of claim 139, wherein said method further comprises administering to said patient one or more other therapies.
144. A pharmaceutical composition comprising an enzymatic nucleic acid molecule of any of claims 55-58 in a pharmaceutically acceptable carrier.
145. A pharmaceutical composition comprising an antisense nucleic acid molecule of claim 59 in a pharmaceutically acceptable carrier.
146. The enzymatic nucleic acid molecule of claim 55, wherein said subunit of KK-is EKK-gamma.
147. The enzymatic nucleic acid molecule of claim 55, wherein said subunit of IKK-is EKK-alpha.
148. The enzymatic nucleic acid molecule of claim 55, wherein said subunit of IKK-is IKK-beta.
149. A method of administering to a cell an enzymatic nucleic acid molecule of any of claims 55-57 comprising contacting said cell with the enzymatic nucleic acid molecule under conditions suitable for said administration.
150. The method of claim 149, wherein said cell is a mammalian cell.
151. The method of claim 149, wherein said cell is a human cell.
152. The method of claim 149, wherein said administration is in the presence of a delivery reagent.
153. The method of claim 152, wherein said delivery reagent is a lipid.
154. The method of claim 153, wherein said lipid is a cationic lipid.
155. The method of claim 153, wherein said lipid is a phospholipid.
156. The method of claim 152, wherein said delivery reagent is a liposome.
157. A nucleic acid molecule that down regulates expression of a prostaglandin D2 receptor (PTGDR) gene.
158. The nucleic acid molecule of claim 157, wherein said nucleic acid molecule is an enzymatic nucleic acid molecule.
159. The nucleic acid molecule of claim 157, wherein said nucleic acid molecule is an antisense nucleic acid molecule.
160. The enzymatic nucleic acid molecule of claim 158, wherein said enzymatic nucleic acid molecule comprises a sequence selected from the group of sequences consisting of SEQ ID NOs: 11666-13262.
161. The enzymatic nucleic acid molecule of claim 158, wherein said enzymatic nucleic acid molecule comprises at least one binding arm wherein the at least one binding arm comprises a sequence complementary to a sequence selected from the group of sequences consisting of SEQ ED NOs: 4415-5483.
162. The antisense nucleic acid molecule of claim 159, wherein said antisense nucleic acid molecule comprises a sequence complementary to a sequence selected from the group of sequences consisting of SEQ ID NOs: 4415-5483.
163. The nucleic acid molecule of claim 157, wherein said nucleic acid molecule is adapted to treat asthma.
164. The enzymatic nucleic acid molecule of any of claims 158, 160 or 161, wherein said enzymatic nucleic acid molecule has an endonuclease activity to cleave RNA encoded by a PTGDR gene.
165. The enzymatic nucleic acid molecule of claim 157, wherein said enzymatic nucleic acid molecule is in a hammerhead configuration.
166. The enzymatic nucleic acid molecule of claim 157, wherein said enzymatic nucleic acid molecule is in an Inozyme configuration.
167. The enzymatic nucleic acid molecule of claim 157, wherein said enzymatic nucleic acid molecule is in a Zinzyme configuration.
168. The enzymatic nucleic acid molecule of claim 157, wherein said enzymatic nucleic acid molecule is in a DNAzyme configuration.
169. The enzymatic nucleic acid molecule of claim 157, wherein said enzymatic nucleic acid molecule is in a G-cleaver configuration.
170. The enzymatic nucleic acid molecule of claim 157, wherein said enzymatic nucleic acid molecule is in an Amberzyme configuration.
171. The enzymatic nucleic acid molecule of claim 165, wherein said hammerhead configuration comprises a sequence complementary to a sequence selected from the group of sequences consisting of SEQ ED NOs: 4415-4641.
172. The enzymatic nucleic acid molecule of claim 165, wherein said hammerhead configuration comprises a sequence selected from the group of sequences consisting of SEQ ED NOs: 11666-11892.
173. The enzymatic nucleic acid molecule of claim 166, wherein said Inozyme configuration comprises a sequence complementary to a sequence selected from the group of sequences consisting of SEQ ED NOs: 4642-5017.
174. The enzymatic nucleic acid molecule of claim 166, wherein said Inozyme configuration comprises a sequence selected from the group of sequences consisting of SEQ ED NOs: 11893-12268.
175. The enzymatic nucleic acid molecule of claim 167, wherein said Zinzyme configuration comprises a sequence complementary to a sequence selected from the group of sequences consisting of SEQ ID NOs: 5018-5248.
176. The enzymatic nucleic acid molecule of claim 167, wherein said Zinzyme configuration comprises a sequence selected from the group of sequences consisting of SEQ ID NOs: 12269-12499.
177. The enzymatic nucleic acid molecule of claim 168, wherein said DNAzyme configuration comprises a sequence complementary to a sequence selected from the group of sequences consisting of SEQ ED NOs: 4415-5294.
178. The enzymatic nucleic acid molecule of claim 168, wherein said DNAzyme configuration comprises a sequence selected from the group of sequences consisting of SEQ ED NOs: 12500-12842.
179. The enzymatic nucleic acid molecule of claim 170, wherein said Amberzyme configuration comprises a sequence complementary to a sequence selected from the group of sequences consisting of SEQ ED NOs: 5018-5248, and 5295-5483.
180. The enzymatic nucleic acid molecule of claim 170, wherein said Amberzyme configuration comprises a sequence selected from the group of sequences consisting of SEQ ED NOs: 12843-13262.
181. The enzymatic nucleic acid molecule of any of claims 158, 160 or 161, wherein said enzymatic nucleic acid molecule comprises between 8 and 100 bases complementary to a RNA molecule encoded by a PTGDR gene.
182. The enzymatic nucleic acid molecule of any of claims 158, 160 or 161, wherein said enzymatic nucleic acid molecule comprises between 14 and 24 bases complementary to a RNA molecule encoded by a PTGDR gene.
183. The enzymatic nucleic acid molecule of any of claims 158, 160 or 161, wherein said enzymatic nucleic acid molecule is chemically synthesized.
184. The antisense nucleic acid molecule of claim 159, wherein said antisense nucleic acid molecule is chemically synthesized.
185. The enzymatic nucleic acid molecule of any of claims 158, 160 or 161, wherein said enzymatic nucleic acid molecule comprises at least one 2 '-sugar modification.
186. The antisense nucleic acid molecule of claim 159, wherein said antisense nucleic acid molecule comprises at least one 2 '-sugar modification.
187. The enzymatic nucleic acid molecule of any of claims 158, 160 or 161, wherein said enzymatic nucleic acid molecule comprises at least one nucleic acid base modification.
188. The antisense nucleic acid molecule of claim 159, wherein said antisense nucleic acid molecule comprises at least one nucleic acid base modification.
189. The enzymatic nucleic acid molecule of any of claims 158, 160 or 161, wherein said enzymatic nucleic acid molecule comprises at least one phosphate backbone modification.
190. The antisense nucleic acid molecule of claim 159, wherein said antisense nucleic acid molecule comprises at least one phosphate backbone modification.
191. A mammalian cell comprising the enzymatic nucleic acid molecule of any of claims 158, 160 or 161.
192. The mammalian cell of claim 191, wherein said mammalian cell is a human cell.
193. A method of reducing PTGDR activity in a cell, comprising contacting said cell with the enzymatic nucleic acid molecule of any of claims 158, 160 or 161, under conditions suitable for said reduction.
194. A method of reducing PTGDR activity in a cell, comprising contacting said cell with the antisense nucleic acid molecule of claim 159 under conditions suitable for said reduction.
195. A method of treatment of a patient having a condition associated with the level of PTGDR, comprising contacting cells of said patient with the enzymatic nucleic acid molecule of any of claims 158, 160 or 161, under conditions suitable for said treatment.
196. A method of treatment of a patient having a condition associated with the level of PTGDR, comprising contacting cells of said patient with the antisense nucleic acid molecule of claim 159, under conditions suitable for said treatment.
197. The method of claim 193 further comprising the use of one or more drug therapies under conditions suitable for said treatment.
198. The method of claim 194 further comprising the use of one or more drug therapies under conditions suitable for said treatment.
199. The method of claim 195 further comprising the use of one or more drug therapies under conditions suitable for said treatment.
200. The method of claim 196 further comprising the use of one or more drug therapies under conditions suitable for said treatment.
201. A method of cleaving a RNA molecule encoded by a PTGDR gene comprising contacting the enzymatic nucleic acid molecule of any of claims 158, 160 or 161 with said RNA molecule encoded by a PTGDR gene under conditions suitable for the cleavage.
202. The method of claim 201 , wherein said cleavage is carried out in the presence of a divalent cation.
203. The method of claim 202, wherein said divalent cation is Mg2+.
204. The enzymatic nucleic acid molecule of any of claims 158, 160 or 161, wherein said enzymatic nucleic acid comprises a cap structure, wherein the cap structure is at the 5 '-end, 3 '-end, or both the 5 '-end and the 3 '-end.
205. The antisense nucleic acid molecule of claim 159, wherein said antisense nucleic acid comprises a cap structure, wherein the cap structure is at the 5 '-end, 3 '-end, or both the 5 '-end and the 3 '-end.
206. The enzymatic nucleic acid molecule of claim 204, wherein the cap structure at the 5'-end, 3'-end, or both the 5'-end and the 3'-end comprises a 3',3'-linked or 5',5'-linked deoxyabasic ribose derivative.
207. The antisense nucleic acid molecule of claim 205, wherein the cap structure at the 5'-end, 3'-end, or both the 5'-end and the 3'-end comprises a 3',3'-linked or 5', 5'- linked deoxyabasic ribose derivative.
208. The method of claim 193, wherein said enzymatic nucleic acid molecule is in a Zinzyme configuration.
209. An expression vector comprising a nucleic acid molecule encoding at least one enzymatic nucleic acid molecule of claim 158 or claim 160 in a manner that allows expression ofthe nucleic acid molecule.
210. A mammalian cell comprising the expression vector of claim 209.
211. The mammalian cell of claim 210, wherein said mammalian cell is a human cell.
212. The expression vector of claim 209, wherein said enzymatic nucleic acid molecule is in a hammerhead configuration.
213. The expression vector of claim 209, wherein said expression vector further comprises a sequence for an antisense nucleic acid molecule complementary to a RNA molecule encoded by a PTGDR gene.
214. The expression vector of claim 209, wherein said expression vector comprises a nucleic acid sequence encoding two or more of said enzymatic nucleic acid molecules, which can be the same or different.
215. The expression vector of claim 214, wherein said expression vector further comprises a sequence encoding an antisense nucleic acid molecule complementary to a RNA molecule encoded by a PTGDR gene.
216. A method for treatment of an allergic condition comprising the step of administering to a patient the enzymatic nucleic acid molecule of any of claims 156-159 under conditions suitable for said treatment.
217. The method of claim 216, wherein said allergic condition is asthma, allergic rhinitis, or atopic dermatitis.
218. A method for treatment of an allergic condition comprising administering to a patient the antisense nucleic acid molecule of claim 159 under conditions suitable for said treatment.
219. The method of claim 218, wherein said allergic condition is asthma, allergic rhinitis, or atopic dermatitis.
220. The method of claim 216, wherein said enzymatic nucleic acid molecule is in a Zinzyme configuration.
221. The method of claim 216, wherein said method further comprises administering to said patient one or more other treatment therapies.
222. The method of claim 218, wherein said method further comprises administering to said patient one or more other treatment therapies.
223. The enzymatic nucleic acid molecule of any of claims 158, 160 or 161, wherein said enzymatic nucleic acid molecule comprises at least five ribose residues, at least ten 2'-O-methyl modifications, and a 3'- end modification.
224. The enzymatic nucleic acid molecule of claim 223, wherein said enzymatic nucleic acid molecule further comprises phosphorothioate linkages on at least three ofthe 5' terminal nucleotides.
225. The nucleic acid molecule of claim 223, wherein said 3'- end modification is a 3'- 3' inverted abasic moiety.
226. The method of claim 197 wherein said other drug therapies are bronchodilators, anti-inflammatories, adenosine inhibitors, or adenosine Al receptor inhibitors.
227. A pharmaceutical composition comprising an enzymatic nucleic acid molecule of any of claims 158, 160 or 161.
228. A pharmaceutical composition comprising an antisense nucleic acid molecule of claim 159.
229. A method of administering to a mammal the nucleic acid molecule of claim 157, comprising contacting said mammal with the nucleic acid molecule under conditions suitable for said administration.
230. The method of claim 229, wherein said mammal is a human.
231. The method of claim 229 wherein said administration is in the presence of a delivery reagent.
232. The method of claim 231 , wherein said delivery reagent is a lipid.
233. The method of claim 232, wherein said lipid is a cationic lipid.
234. The method of claim 232, wherein said lipid is a phospholipid.
235. The method of claim 231 , wherein said delivery reagent is a liposome.
PCT/US2002/010512 2000-02-11 2002-04-03 Modulation of gene expression associated with inflammation proliferation and neurite outgrowth, using nucleic acid based technologies WO2002081628A2 (en)

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AU2002307099A AU2002307099A1 (en) 2001-04-05 2002-04-03 Modulation of gene expression associated with inflammation proliferation and neurite outgrowth, using nucleic acid based technologies
EP02763926A EP1386004A4 (en) 2001-04-05 2002-04-03 Modulation of gene expression associated with inflammation proliferation and neurite outgrowth, using nucleic acid based technologies
US10/471,271 US20070026394A1 (en) 2000-02-11 2002-04-03 Modulation of gene expression associated with inflammation proliferation and neurite outgrowth using nucleic acid based technologies
US10/206,693 US20050261212A1 (en) 2000-02-11 2002-07-26 RNA interference mediated inhibition of NOGO and NOGO receptor gene expression using short interfering RNA
US10/430,882 US20030203870A1 (en) 2000-02-11 2003-05-06 Method and reagent for the inhibition of NOGO and NOGO receptor genes
US10/923,142 US20050182008A1 (en) 2000-02-11 2004-08-20 RNA interference mediated inhibition of NOGO and NOGO receptor gene expression using short interfering nucleic acid (siNA)
US11/255,139 US20060154271A1 (en) 2001-04-05 2005-10-20 Enzymatic nucleic acid treatment of diseases or conditions related to levels of IKK-gamma and PKR

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US29441201P 2001-05-29 2001-05-29
US60/294,412 2001-05-29
US31531501P 2001-08-28 2001-08-28
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US20030191077A1 (en) 2003-10-09
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